Oxindolinylamide derivatives for inhibiting NLRP3 and their use

Abstract

The present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof. Further provided are, for example, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, as an inhibitor of NLRP3 useful for the treatment of diseases and disorders inhibited by said protein, pharmaceutical compositions comprising the same, methods of preparation, as well as methods of use and treatment. JPEG2025516719000220.jpg32170

Description

Technical Field

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 341,614, filed May 13, 2022, the entire content of which is incorporated herein by reference in its entirety.

Background Art

[0002] The innate immune response is mediated by different types of receptors called pattern recognition receptors (PRRs). PRRs recognize the presence of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). When these receptors are involved, activation of downstream inflammatory pathways that help resolve damage is triggered. However, in many cases, this activation can be uncontrolled and lead to disease.

[0003] The inflammasome represents a class of PRRs that are important components of the innate immune response. Activation of the inflammasome triggers a cascade of events that release IL-1β, IL-18, and promote an inflammatory form of cell death called pyroptosis, which is induced by activation of gasdermin. Pyroptosis is a unique form of inflammatory cell death that leads to the release of not only cytokines but also other intracellular components that promote a broader immune response in both the innate and adaptive immune systems. Thus, inflammasome activation is a major regulator of the inflammatory cascade.

[0004] NLRP3 is the most characterized inflammasome and has been shown to be important in innate immune responses and inflammatory responses. Some other NLR complexes, such as NLRC4, are activated under very specific circumstances, while NLRP3 can be activated by a number of stimuli and should be regarded as a sensor of intracellular homeostasis imbalance. Therefore, its exact function is indispensable. In addition to playing a role in the host's immune defense, dysregulation of NLRP3 is associated with the etiology of many inflammatory disorders. These include genetic diseases such as cryopyrin-associated periodic syndromes (CAPS) caused by gain-of-function mutations in the NLRP3 gene, as well as many common neurological and systemic diseases. Importantly, preclinical evidence has shown that hyperactivation of NLRP3 plays an important role in a number of inflammatory and degenerative diseases, including NASH, atherosclerosis and other cardiovascular diseases, Alzheimer's disease, Parkinson's disease, diabetes, gout, and many other autoinflammatory diseases. Therefore, there is an unmet need in the art to develop small molecules to modulate NLRP3 activity for the treatment of various diseases and disorders.

SUMMARY OF THE INVENTION

[0005] In one aspect, the present disclosure provides oxindolinylamide compounds of formula (I):

CHEMICAL

[0006] In some embodiments, provided is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, and one or more pharmaceutically acceptable excipients.

[0007] In some embodiments, provided is a method for preparing a compound of formula (I). In other embodiments, provided is an intermediate suitable for use in a method for preparing a compound of formula (I).

[0008] In yet another aspect, provided is a method of doing so in a subject in need of treating a disease or disorder, the method comprising administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof.

[0009] In yet another aspect, provided is a method of inhibiting NLRP3 activity in a cell, the method comprising contacting the cell with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof.

[0010] Definitions Unless otherwise defined, the following terms used in this specification and the claims have the following meanings as set forth below.

[0011] "Aliphatic hydrocarbon" refers to an acyclic hydrocarbon group that contains carbon atoms in its backbone and may further contain one or more double or triple bonds within the hydrocarbon backbone. Such groups include alkyl, alkenyl, and alkynyl groups as defined herein.

[0012] As used herein, "alkyl," "C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl," or "C 1 -C 6 alkyl" refers to a C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 linear (straight-chain) saturated aliphatic hydrocarbon group, and a C 3 , C 4 , C 5or C that does not contain a double or triple bond in its skeleton 6 is intended to include a branched saturated aliphatic hydrocarbon group. For example, C 1 -C 6 alkyl is intended to include C 1 -C 2 -C 3 -C 4 -C 5 -C 6 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl, etc., and include moieties having 1 to 6 carbon atoms. In some embodiments, the straight-chain or branched alkyl has 6 or fewer carbon atoms in its skeleton (e.g., for a straight chain, C 1 -C 6 , for a branched chain, C 3 -C 6 ), and in another embodiment, the straight-chain or branched alkyl has 4 or fewer carbon atoms in its skeleton.

[0013] As used herein, the term "optionally substituted alkyl" refers to unsubstituted alkyl or substituted alkyl having a specified substituent that replaces one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphanate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0014] As used herein, "alkenyl", "C 2 , C 3 , C 4 , C 5 , or C 6 alkenyl", or "C 2 -C 6 alkenyl" is intended to include an unsaturated aliphatic hydrocarbon group having 2 to 6 carbon atoms and at least one double bond in its backbone, C 2 , C 3 , C 4 , C 5 , or C 6 straight-chain (linear) alkenyl groups, and C 3 , C 4 , C 5 , or C 6It contains a branched alkenyl group. For example, the term "alkenyl" includes linear alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl), and branched alkenyl groups. In some embodiments, the linear or branched alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., for a straight chain, C 2 -C 6 , and for a branched chain, C 3 -C 6 ). The term "C 2 -C 6 " includes alkenyl groups containing 2 to 6 carbon atoms in their backbone, and the term "C 3 -C 6 " includes alkenyl groups containing 3 to 6 carbon atoms in their backbone.

[0015] As used herein, the term "optionally substituted alkenyl" refers to unsubstituted alkenyl or the above-mentioned substituted alkenyl having one or more substituents that replace one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphanate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0016] As used herein, "alkynyl", "C 2 ", "C 3 ", "C 4 ", "C 5 ", "or C 6 alkynyl", or "C 2 -C 6 alkynyl" is intended to include an unsaturated aliphatic hydrocarbon group containing 2 to 6 carbon atoms and at least one triple bond in its backbone, and C 2 ", "C 3 ", "C 4 ", "C 5 ", "or C 6 linear (straight-chain) unsaturated alkynyl groups, and C 3 ", "C 4 ", "C 5 ", "or C 6 branched unsaturated alkynyl groups. For example, "alkynyl" includes linear alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl), and branched alkynyl groups. In some embodiments, the linear or branched alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for linear, C 3 -C 6 for branched). The term "C 2 -C 6 " includes an alkynyl group containing 2 to 6 carbon atoms in its backbone, and the term "C 3 -C 6 " includes an alkynyl group containing 3 to 6 carbon atoms in its backbone.

[0017] As used herein, the term "optionally substituted alkynyl" refers to unsubstituted alkynyl or substituted alkynyl having, on one or more hydrocarbon backbone carbon atoms, a specified substituent that replaces one or more hydrogen atoms. Such substituents include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphanate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or an aromatic hydrocarbon moiety or a heteroaromatic moiety.

[0018] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, etc.) include both unsubstituted moieties and moieties having one or more of the specified substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups such as 2,2,6,6 - tetramethyl - piperidinyl and 2,2,6,6 - tetramethyl - 1,2,3,6 - tetrahydropyridinyl.

[0019] As used herein, the term "cycloalkyl" refers to a ring having 3 to 12 carbon atoms (e.g., C 3 -C 12 、C 3 -C 10 、or C 3 -C 8Refers to a non-aromatic saturated or partially unsaturated cyclic hydrocarbon that is a monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) system having ). Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyls, only one of the rings in the cycloalkyl needs to be non-aromatic.

[0020] As used herein, the term "optionally substituted cycloalkyl" refers to an unsubstituted cycloalkyl or a substituted cycloalkyl having one or more substituents that replace one or more hydrogen atoms on one or more carbon or heteroatoms. Such substituents include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphanate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or an aromatic hydrocarbon moiety or a heteroaromatic moiety.

[0021] As used herein, the terms "heterocyclyl" or "heterocycloalkyl", unless otherwise specified, refer to a non-aromatic saturated or partially unsaturated 3- to 8-membered monocyclic or bicyclic, 7- to 12-membered bicyclic (fused, bridged, or spiro ring), or 11- to 14-membered tricyclic system (fused, bridged, or spiro ring) having, independently in its backbone, one or more ring heteroatoms (such as O, N, S, P, or Se) selected from the group consisting of nitrogen, oxygen, and sulfur, for example, one, or 1 to 2, or 1 to 3, or 1 to 4, or 1 to 5, or 1 to 6 heteroatoms, or for example, 1, 2, 3, 4, 5, or 6 heteroatoms.Examples of the heterocyclic group include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-azaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3’H-spiro[cyclohexane-1,1’-isobenzofuran]-yl, 7’H-spiro[cyclohexane-1,5’-furo[3,4-b]pyridine]-yl, 3’H-spiro[cyclohexane-1,1’-furo[3,4-c]pyridine]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, etc. In the case of a polycyclic heterocyclic group, only one of the rings in the heterocyclic group needs to be non-aromatic (for example, 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0022] As used herein, the term "optionally substituted heterocyclyl" refers to an unsubstituted heterocyclyl or a substituted heterocyclyl having one or more substituents that replace one or more hydrogen atoms on one or more carbon or heteroatoms. Such substituents include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphanate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or an aromatic hydrocarbon moiety or a heteroaromatic moiety.

[0023] Unless otherwise specifically defined, the term "aryl" or "aromatic hydrocarbon" moiety or group refers to a cyclic C 6 ) having 1 to 3 aromatic hydrocarbon rings, including monocyclic or bicyclic groups such as phenyl (C 6 ) substituted by aryl, C 6 aryl), or naphthyl (C 10 ) 6 -C 14Refers to an aromatic hydrocarbon group (including carbon in the ring skeleton). When containing two aromatic hydrocarbon rings (such as bicyclic), the aromatic hydrocarbon rings of the aryl group may be joined at a single point (e.g., biphenyl) or may be fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, for example, 1 to 5 substituents, at any position of the aryl ring. Exemplary substituents include -H, -halogen, -O-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, -O-(C 2 -C 6 )alkenyl, -O-(C 2 -C 6 )alkynyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, -OH, -OP(O)(OH) 2 、-OC(O)(C 1 -C 6 )alkyl, -C(O)(C 1 -C 6 )alkyl, -OC(O)O(C 1 -C 6 )alkyl, -NH 2 、NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 、-S(O) 2 -(C 1 -C 6 )alkyl, -S(O)NH(C 1 -C 6 )alkyl, and -S(O)N((C 1 -C 6 )alkyl) 2Examples include, but are not limited to these. The substituents themselves may be optionally substituted. Further, when containing two or more fused aromatic hydrocarbon rings, the aryl group as defined herein may have a saturated or partially unsaturated cycloalkyl or heterocyclic ring fused to a completely unsaturated aromatic hydrocarbon ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, 10,11-dihydro-5H-dibenzo[a,d][7]annulenyl, and the like.

[0024] Unless otherwise specifically defined, a "heteroaryl" or "heterocyclic aromatic" moiety or group refers to a monocyclic or polycyclic aromatic radical of 5 to 14 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, Se, or B within the aromatic ring system, with the remaining ring atoms being C. Heteroaryl as defined herein also means a bicyclic heterocyclic aromatic group where the ring heteroatom is selected from N, O, S, P, Se, or B. Heteroaryl as defined herein also means a tricyclic heterocyclic aromatic group containing one or more ring heteroatoms selected from N, O, S, P, Se, or B. The aromatic radicals are independently optionally substituted with one or more substituents described herein.Examples include frill, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ. 2- pyrrolo[2,1 - b]pyrimidine, dibenzo[b,d]thiophene, pyridin - 2 - one, furo[3,2 - c]pyridinyl, furo[2,3 - c]pyridinyl, 1H - pyrido[3,4 - b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3 - b]pyridinyl, benzothiophenyl, 1,5 - naphthyridinyl, furo[3,2 - b]pyridine, [1,2,4]triazolo[1,5 - a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2 - a]pyrimidinyl, [1,2,4]triazolo[4,3 - b]pyridazinyl, benzo[c][1,2,5]oxadiazole, 1,3 - dihydro - 2H - benzimidazol - 2 - one, 3,4 - dihydro - 2H - pyrazolo[1,5 - b][1,2]oxazinyl, 4,5,6,7 - tetrahydropyrazolo[1,5 - a]pyridinyl, thiazolo[5,4 - d]thiazolyl, imidazo[2,1 - b][1,3,4]thiadiazolyl, thieno[2,3 - b]pyrrolyl, 3H - indolyl, and derivatives thereof, including but not limited to these. Further, when containing two or more fused rings, the heteroaryl group as defined herein may have one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings fused to a fully unsaturated aromatic ring, for example, a 5 - membered heterocyclic aromatic ring containing 1 to 3 heteroatoms selected from N, O, S, P, Se, or B, or a 6 - membered heterocyclic aromatic ring containing 1 to 3 nitrogens, and the saturated or partially unsaturated cycloalkyl or heterocyclic ring contains 0 to 4 heteroatoms selected from N, O, S, P, Se, or B and is optionally substituted with one or more oxo (i.e., C = O groups). In a heteroaryl ring system containing more than two fused rings, the saturated or partially unsaturated cycloalkyl or heterocyclic ring may be further fused to the saturated or partially unsaturated cycloalkyl or heterocyclic ring described herein.Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-oneyl, 7,8-dihydro-1H-pyrazolo[3,4-c]pyridin-7-oneyl, 1,6 ... hydro-6H-pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidine, pyrazolo[1,5-a]pyrimidin-7(4H)-one, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-one, or benzo[c][1,2]oxaborol-1(3H)-oleyl.

[0025] "Arylalkyl" or "aralkyl" is a C 1 -C 6 Optionally substituted C attached to an alkyl group 6 -C 10 Aryl group, or C 1 -C 6 Arylalkyl refers to an optionally substituted 5-6 membered heteroaryl group attached to an alkyl group, where the point of attachment to the parent molecule is on the alkyl group. In some embodiments, arylalkyl is an aryl-C 1-6 It is an alkyl.

[0026] A cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring may be substituted at one or more ring positions (e.g., a heteroatom such as a ring-forming carbon or N) with substituents such as those described above, e.g., alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphanate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups may also be fused or bridged to a cycloalkyl or heterocyclic ring that is not aromatic so as to form a polycyclic system (e.g., methylenedioxyphenyl such as tetralin, benzo[d][1,3]dioxol-5-yl) where the point of attachment to the parent molecule is on the aromatic aryl or heteroaryl ring.

[0027] As used herein, the term "divalent radical" refers to a group such as an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group as defined herein having two points of attachment.

[0028] As used herein, the terms "nitrile" and "cyano" are used interchangeably herein and each refers to -CN.

[0029] As used herein, the term "carboxylic acid" refers to a -CO 2 H group.

[0030] As used herein, the term "tetrazole" refers to each of the following tautomeric structures:

Chemical formula

[0031] As used herein, the term "hydroxy" or "hydroxyl" refers to an -OH group.

[0032] As used herein, the term "amino" refers to a primary, secondary, or tertiary amine. In some embodiments, amino is -NH 2 , C 1 -C 6 alkylamino-, C 1 -C 6 dialkylamino-, C 6 -C 10 arylamino-, C 6 -C 10 diarylamino-, or (C 1 -C 6 (alkyl)(C 6 -C 10 aryl)amino-.

[0033] As used herein, the terms "halo" or "halogen" are used interchangeably and refer to fluoro, chloro, bromo, and iodo.

[0034] The terms "haloalkyl" or "haloalkoxyl" refer to an alkyl or alkoxyl substituted with one or more halogen atoms.

[0035] As used herein, the term "optionally substituted haloalkyl" refers to an unsubstituted haloalkyl having a designated substituent that replaces one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphanate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or can include an aromatic or heteroaromatic moiety.

[0036] As used herein, the terms "alkoxy" or "alkoxyl" include substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy groups or alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentyloxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. An alkoxy group may be substituted with a group such as, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphanate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0037] As used herein, the term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced with a selection from the recited groups, provided that the replacement does not exceed the normal valence of the specified atom and results in a stable compound. When the substituent is an oxo group (i.e., a C=O group), two hydrogen atoms on the atom are replaced. An oxo substituent is not present on an aromatic moiety. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). "Stable compound" and "stable structure" mean compounds that are sufficiently robust to withstand isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

[0038] When it is shown that a bond to a substituent crosses a bond connecting two atoms within a ring, such a substituent can be bonded to any atom within the ring. When a substituent is listed without indicating the atom to which such a substituent is bonded to the remainder of a compound of a given formula, such a substituent can be bonded through any atom of such a formula. Substituents and / or variable combinations are permitted only if such combinations result in a stable compound.

[0039] Any component of a compound or any variable (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6’ , R 6” , R 7 , Z, L 1 , L 2) If it appears two or more times, its definition in each occurrence is independent of its definition in all other occurrences. Thus, for example, if a group is shown to be substituted with from 0 to 3 R moieties, the group may optionally be substituted with up to 2 R moieties, and at each occurrence R is selected independently of the definition of R. Also, substituents and / or variable combinations are permitted, but only if such combinations result in stable compounds.

[0040] Compounds that have the same molecular formula but differ in the nature or order of bonding of their atoms or in the arrangement of those atoms in space are called "isomers". Isomers that differ in the arrangement of atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are mirror images that cannot be superimposed on each other are called "enantiomers". Compounds having two or more chiral (asymmetric) centers can exist either as individual diastereomers or as a mixture of diastereomers called a "mixture of diastereomers". Similarly, compounds having only one chiral (asymmetric) center can exist either as individual enantiomers or as a mixture of enantiomers. A mixture containing a (substantially equal proportion of) mixture of diastereomers or enantiomers is called a "racemic mixture". Absolute configuration refers to the arrangement in space of the substituents attached to a chiral center. The substituents attached to the chiral center under consideration are ranked according to the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; Erratum 511, Cahn et al., Angew. Chem. 1966, 78, 413, Cahn and Ingold, J. Chem. Soc. 1951 (London), 612, Cahn et al., Experientia 1956, 12, 81, Cahn, J. Chem. Educ. 1964, 41, 116). Methods for the determination of stereochemistry and the separation of stereoisomers, for example by synthesis from optically active starting materials or the resolution of racemic forms, are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001).

[0041] As used herein, the term "geometric isomer" means a diastereomer whose existence is due to rotational hindrance around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished by the prefixes cis and trans or Z and E, which indicate whether the groups are located on the same or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog ranking rules. Some of the compounds of the present disclosure may have geometric isomer centers (E- and Z-isomers). It is to be understood that the present disclosure encompasses all geometric isomers and mixtures thereof.

[0042] "Salt" includes any and all salts, including pharmaceutically acceptable salts.

[0043] As used herein, the term "pharmaceutically acceptable salt" refers to compounds of the present disclosure in which the parent compound is modified by making its acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, formic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolurilsulfanic acid, hexylresorcinolic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, trifluoroacetic acid, and generally occurring amino acids such as glycine, alanine, phenylalanine, arginine, etc., but are not limited thereto.

[0044] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, and the like. The present disclosure also includes salts formed when an acidic proton present in the parent compound is replaced by any of a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, methanamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0045] Salts can be formed between an anion and a positively charged group (e.g., amino) on the substituted compounds disclosed herein. As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate). Similarly, salts can also be formed between a cation and a negatively charged group (e.g., carboxylate) on the substituted compounds disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and ammonium cations such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include their salts containing a quaternary nitrogen atom. It is understood that in the salt form, the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

[0046] In some embodiments, the pharmaceutically acceptable salts are sodium salts, potassium salts, calcium salts, magnesium salts, diethylamine salts, choline salts, meglumine salts, benzathine salts, tromethamine salts, ammonia salts, arginine salts, or lysine salts.

[0047] It should be understood that all references to pharmaceutically acceptable salts include solvate (solvent addition form) or crystalline form (polymorph) of the same salt as defined herein.

[0048] The compounds are also provided herein as "neutral" compounds. "Neutral" and "free base" are used interchangeably herein to refer to compounds that are not salts. All references to the neutral (free base) form are understood to include solvate adduct forms (solvates) or crystalline forms (polymorphs) of the same neutral (free base) compound as defined herein. For purposes of illustration, a neutral compound can be converted to the corresponding pharmaceutically acceptable salt of the compound using conventional techniques in the art (e.g., by saponifying an ester to a carboxylate salt or hydrolyzing an amide to form the corresponding carboxylic acid and then converting the carboxylic acid to a carboxylate salt). In some embodiments, the solvate or crystalline form has different properties compared to the neutral compound.

[0049] As used herein, the term "solvate" means a solvate adduct form that contains a solvent in either a stoichiometric or non-stoichiometric amount. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state and thus form solvates. When the solvent is water, the solvate formed is a "hydrate", and when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of a substance, and water retains its molecular state as H 2 O, for example, as a hydrate such as a hemihydrate, monohydrate, dihydrate, or trihydrate. It should be understood that the compounds of the present disclosure can exist in either a hydrated or non-hydrated (anhydrous) form, or as a solvate with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0050] An "inclusion compound" is a host molecule in which a guest molecule (i.e., a compound of formula (I)) is within a cage formed by the host molecule or the lattice of the host molecule.

[0051] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another, which results in a formal shift of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomer sets in solution. In a solution where tautomerism is possible, a chemical equilibrium of tautomers will be achieved. The exact ratio of tautomers depends on several factors including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerism is called tautomerism. Of the various possible types of tautomerism, two are commonly observed. In keto-enol tautomerism, a simultaneous shift of electrons and hydrogen atoms occurs. Ring-chain tautomerism results from the reaction of an aldehyde group (-CHO) in a sugar molecule with one of the hydroxy groups (-OH) in the same molecule, yielding a cyclic (ring-shaped) form as shown by glucose. Examples of tautomeric forms include, for example, the following tautomer pairs: keto / enol (shown below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro, etc., and keto form, enol form, and enolate form. [Chemical formula]

[0052] It should be understood that the compounds of the present disclosure may be shown as different tautomers. Also, when a compound has a tautomeric form, it is intended that all tautomeric forms are included within the scope of the present disclosure, and it should be understood that the name of the compound does not exclude any tautomeric form. It should be understood that a particular tautomer may have a higher level of activity than other tautomers.

[0053] Any particular compound of one of the formulas disclosed herein may exhibit polymorphs (polymorphic forms), and it should also be understood that the present disclosure encompasses all such forms, or mixtures thereof. Crystalline materials can generally be analyzed using conventional techniques such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, solution and / or solid nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis. In some embodiments, polymorphs may have different properties compared to the neutral compound.

[0054] Any one of the compounds of the formulas disclosed herein can be administered in the form of a prodrug that is decomposed in a human or animal body to release the compounds of the present disclosure. The prodrug can be used to modify the physical properties and / or pharmacokinetic properties of the compounds of the present disclosure. Examples of prodrugs include derivatives containing alkyl or acyl substituents that are cleavable in vivo at ester or amide groups in any one of the formulas disclosed herein. Suitable prodrugs of any one of the compounds of the formulas disclosed herein are based on a reasonable medical judgment that they are suitable for administration to the human or animal body without undesirable pharmacological activity and without excessive toxicity.Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, p. 309 - 396, edited by K. Widder, et al. (Academic Press, 1985), b) Design of Pro - drugs, edited by H. Bundgaard, (Elsevier, 1985), c) A Textbook of Drug Design and Development, edited by Krogsgaard - Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro - drugs,” by H. Bundgaard p. 113 - 191 (1991), d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1 - 38 (1992), e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988), f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984), g) T. Higuchi and V. Stella, “Pro - Drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Volume 14, and h) E. Roche (editor), “Bioreversible Carriers in Drug Design,” Pergamon Press, 1987.

[0055] Suitable prodrugs of any one of the compounds of the formulas disclosed herein having a hydroxy group are, for example, esters or ethers cleavable in vivo. An in vivo cleavable ester or ether of any one of the compounds of the formulas disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether that is cleaved in a human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include inorganic esters such as phosphate esters (including phosphoramidocyclic esters). Even more suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include C 1 -C 10 alkanoyl groups such as acetyl group, benzoyl group, phenylacetyl group, and substituted benzoyl groups and phenylacetyl groups, C 1 -C 10 alkoxycarbonyl groups such as ethoxycarbonyl group, N,N-(C 1 -C 6 alkyl)2-carbamoyl group, 2-dialkylaminoacetyl group, and 2-carboxyacetyl group. Examples of ring substituents on the phenylacetyl group and benzoyl group include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1 -C 4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for the hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl group and pivaloyloxymethyl group.

[0056] Suitable pharmaceutically acceptable prodrugs of any one of the compounds of the formulas disclosed herein having a carboxy group are, for example, its amides cleavable in vivo, such as amines such as ammonia, C 1 - 4 alkylamines such as methylamine, dimethylamine, N-ethyl-N-methylamine or diethylamine, (C 1 -C4 (alkyl) 2 -amine, such as C of 2-methoxyethylamine 1 -C 4 alkoxy-C 2 -C 4 alkylamine, phenyl-C such as benzylamine 1 -C 4 alkylamine, and amides formed from amino acids such as glycine or their esters.

[0057] A suitable pharmaceutically acceptable prodrug of any one of the compounds of the formula disclosed herein having an amino group is, for example, its amide derivative cleavable in vivo. Suitable pharmaceutically acceptable amides from the amino group include C 1 -C 10 alkanoyl groups, such as acetyl, benzoyl, phenylacetyl, and amides formed from substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1 -C 4 alkyl)piperazin-1-ylmethyl.

[0058] The in vivo effect of any one of the compounds of the formula disclosed herein may be exerted in part by one or more metabolites formed in the human or animal body after administration of any one of the compounds of the formula disclosed herein. As described herein, the in vivo effect of any one of the compounds of the formula disclosed herein may also be exerted by the metabolism of the precursor compound (prodrug).

[0059] As used herein, the term "isotope derivative" refers to a derivative of a compound in which one or more atoms are isotopically enriched or labeled. For example, an isotope derivative of a compound of formula (I) is isotopically enriched or labeled with respect to one or more isotopes as compared to the corresponding compound of formula (I).

[0060] As used herein, the terms "pharmaceutical composition" or "pharmaceutical formulation" are used interchangeably herein and refer to a formulation containing a compound of formula (I) in a form suitable for administration to a subject, and a pharmaceutically acceptable carrier, diluent, adjuvant, or excipient, or a combination thereof. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form can be in any of a variety of forms, including, for example, capsules, IV bags, tablets, a single pump in an aerosol inhaler, or vials. The amount of the active ingredient in the unit dosage composition can vary according to the particular treatment involved. A variety of routes of administration are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants as required.

[0061] As used herein, the term "pharmaceutically acceptable" refers to compounds, anions, cations, materials, compositions, carriers, and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment, without excessive toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0062] As used herein, the terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" are used interchangeably herein and generally mean excipients that are safe, non-toxic, and not biologically or otherwise undesirable and are useful in the preparation of pharmaceutical compositions, including excipients acceptable for veterinary use as well as for human pharmaceutical use. "Pharmaceutically acceptable excipient" as used herein and in the claims includes both one and more than one such excipient.

[0063] Unless otherwise specified, any description of a method of treatment is to be understood to include the use of a compound (e.g., a compound of formula (I)) for providing such treatment as described herein. Unless otherwise specified, any description of a method of treatment is to be further understood to include the use of a compound for preparing a medicament for treating such a condition. Treatment includes treatment of humans or non-human animals, including rodent and other disease models. As used herein, the term "subject" is interchangeable with the term "subject in need thereof", both of which refer to a subject having a disease or disorder or having an increased risk of developing a disease or disorder.

[0064] As used herein, "subject" is a mammal. The mammal can be, for example, a human or a suitable non-human mammal such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. In one embodiment, the mammal is a human. The subject in need thereof can be a subject previously diagnosed or identified as having a disease or disorder disclosed herein. The subject in need thereof can also be a subject suffering from a disease or disorder disclosed herein. Alternatively, the subject in need thereof can be a subject at high risk of developing such a disease or disorder as compared to the general population (i.e., a subject having a tendency to develop such a disorder as compared to the general population). The subject in need thereof can have a refractory or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject can be resistant at the start of treatment or can become resistant during treatment. In some embodiments, the subject in need of treatment has received and failed all known effective treatments for a disease or disorder disclosed herein. In some embodiments, the subject in need of treatment has received at least one prior treatment. "Subject" and "patient" are used interchangeably herein.

[0065] As used herein, the terms "treating" or "treatment" refer to the management and care of a subject for the purpose of combating a disease, condition, or disorder, and includes "therapeutic treatment" (i.e., "treating therapeutically") to relieve the disease, condition, or disorder from which the subject suffers, by administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, or the subject is diagnosed as having or is predisposed to the symptoms or complications of a disease, condition, or disorder, but the symptoms have not yet manifested, a disease, condition, or disorder can be excluded (or a disease, condition, or disorder can be prevented ("preventive treatment"; "treating preventively")). The term "treatment" can also include the treatment of cells in vitro or in animal models. Thus, "treating" or "treatment" of a condition, disorder, or state includes: (1) preventing or delaying the appearance of clinical symptoms of a condition, disorder, or state that may afflict or be predisposed to a human having the condition, disorder, or state, (2) inhibiting a condition, disorder, or state, i.e., preventing the onset or recurrence (in the case of maintenance therapy) of a disease or at least one of its clinical or non-clinical symptoms, or reducing or delaying it, or (3) reducing or alleviating a disease, i.e., causing regression of at least one of a condition, disorder, or state, or its clinical or non-clinical symptoms.

[0066] In some embodiments, treating a disease or disorder is not preventing the disease or disorder.

[0067] As used herein, the term "therapeutically effective amount" refers to the amount of a compound that treats or ameliorates an identified disease or condition with which a subject is afflicted, or that demonstrates a detectable therapeutic or inhibitory effect, and "prophylactically effective amount" refers to the amount of a compound that prevents an identified disease or condition in a subject diagnosed as having or predisposed to the disease or condition but not yet symptomatic. "Therapeutically effective amount" and "prophylactically effective amount" collectively refer to an amount sufficient to treat or prevent an inflammasome-related condition referred to herein, delay the progression of the condition, and / or reduce the symptoms associated with the condition. The magnitude of the dosage for therapeutic or prophylactic purposes of the compounds of formula (I) will of course vary according to well-known medical principles, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration. The effects can be detected by any assay method known in the art. The exact effective amount for a subject will vary depending on the subject's weight, size, and health; the nature and degree of its condition; and the treatment or combination of treatments selected for administration. Notwithstanding the therapeutic or prophylactic effectiveness for a given situation, the effective amount can be determined by routine experimentation within the skill and judgment of the clinician.

[0068] Terms such as "inhibit", "inhibiting", "inhibits", and "inhibitor" refer to the ability of a compound to reduce, delay, halt, or prevent the activity of a particular biological process within a cell (e.g., NLRP3 activity) as compared to a vehicle.

[0069] The phrase "at least one" refers to one example or two or more examples.

[0070] As used herein, the term "about" refers to the recited amount, value, or duration being within ±10% of the recited amount, value, or duration. In some embodiments, "about" refers to within ±10%, ±8%, ±6%, ±5%, ±4%, ±2%, ±1%, or ±0.5% of the recited amount, value, or duration. In some embodiments, "about" refers to within ±10%, ±8%, ±6%, ±5%, ±4%, or ±2% of the recited amount, value, or duration. In some embodiments, "about" refers to within ±5% of the recited amount, value, or duration. In some embodiments, "about" refers to within ±2% or ±1% of the recited amount, value, or duration. For example, in some embodiments, when the term "about" is used in listing a temperature or temperature range, these terms refer to within ±5°C, ±2°C, or ±1°C of the recited temperature or temperature range. In some embodiments, the term "about" refers to within ±2°C of the recited temperature or temperature range.

[0071] The articles "a" and "an" are used in this disclosure to refer to one or more (i.e., at least one) of the grammatical objects of an article.

[0072] Unless otherwise indicated, the term "and / or" is used in this disclosure to mean either "and" or "or".

[0073] Unless otherwise indicated, all percentages and ratios used herein are by weight.

DETAILED DESCRIPTION OF THE INVENTION

[0074] The present disclosure relates to oxindolinylamide derivatives, pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, single stereoisomers, mixtures of stereoisomers, or racemic mixtures of their stereoisomers, tautomers, isotope derivatives, prodrugs, and polymorphs that inhibit NLRP3 activity and are thus useful in methods of treating the human or animal body. The present disclosure also relates to processes for the preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of NLRP3-related diseases, such as inflammation, autoimmune diseases, cancer, infectious diseases, central nervous system diseases or disorders, metabolic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, liver diseases, eye diseases, skin diseases, lymphatic diseases, rheumatic diseases, psychological diseases, graft-versus-host disease, allodynia, or NLRP3-related diseases in a subject determined to have a germ cell or somatic non-silent mutation in NLRP3.

[0075] (1) Compound In one aspect, the present disclosure provides an oxindolinylamide compound of formula (I):

Chemical formula

[0076] In some embodiments of formula (I), R 1 is bromo, chloro, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 12 cycloalkyl, and each R 2 and R 3 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 10Aryl, or 5- to 10-membered heteroaryl, wherein alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 is optionally substituted with alkoxy, or R 2 and R 3 together cyclize to form C 3 -C 12 cycloalkyl or 3- to 12-membered heterocyclyl, and the cycloalkyl or heterocyclyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 is optionally substituted with alkoxy, R 4 is -(n-propyl)-, -(L 1 ) p -(C 3 -C 12 cycloalkyl)-, -(L 1 ) p -(3- to 12-membered heterocyclyl)-, -(L 1 ) p -(C 6 -C 10 aryl)-, or -(L 1 ) p -(5- to 10-membered heteroaryl)-, and each R L1 is independently H, halo, or C 1 -C 3 alkyl, or two R L1The base, together with the atom to which it is attached, forms a C 3 cycloalkyl, and n-propyl, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 cycloalkyl, Z is -(L 2 ) n -(carboxylic acid) or -(L 2 ) n -tetrazole, and each L 2 is independently -(C(R L2 ) 2 -, and further, each R L2 is independently H, halo, or C 1 -C 3 alkyl, or two R L2 groups, together with the atom to which they are attached, form a C 3 cycloalkyl, and alkyl or cycloalkyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 cycloalkyl, each R 5 is independently halo or C 1 -C 6 alkyl, and alkyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 Optionally substituted with alkoxy, or both Rs 5 Cyclize together with the atom to which they are attached to form one or more halo, -CN, -OH, amino, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 Optionally substituted with alkoxy C 3 -C 12 To form cycloalkyl, R 6 Is H, halo, -OH, C 1 -C 6 Alkyl, or C 1 -C 6 Alkoxy, R 6’ Is H, halo, -OH, C 1 -C 6 Alkyl, or C 1 -C 6 Alkoxy, R 6” Is H, halo, -OH, C 1 -C 6 Alkyl, or C 1 -C 6 Alkoxy, R 7 Are independently H or C 1 -C 4 Alkyl, n is an integer of 0, 1, 2, or 3, p is an integer of 0, 1, or 2.

[0077] In some embodiments of formula (I), R 1 is bromo, chloro, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 12 cycloalkyl, and each R 2 and R 3 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, and alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy, or R 2 and R 3 together cyclize to form C 3 -C 12 cycloalkyl or 3- to 12-membered heterocyclyl, and cycloalkyl or heterocyclyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy, and R 4is -(n-propyl)-, -(L 1 ) p -(C 3 -C 12 -cycloalkyl)-, -(L 1 ) p -(3- to 12-membered heterocyclyl)-, -(L 1 ) p -(C 6 -C 10 -aryl)-, or -(L 1 ) p -(5- to 10-membered heteroaryl)-, and each R L1 is independently H, halo, or C 1 -C 3 -alkyl, or two R L1 groups together with the atom to which they are attached form a C 3 -cycloalkyl, and n-propyl, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, or C 3 -cycloalkyl, Z is -(L 2 ) n -(carboxylic acid) or -(L 2 ) n -tetrazole, and each L 2 is independently -(C(R L2 ) 2 -, and further, each R L2 is independently H, halo, or C 1 -C 3 -alkyl, or two R L2 groups together with the atom to which they are attached form a C 3forms a cycloalkyl, and the alkyl or cycloalkyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 cycloalkyl, and each R 5 is independently fluoro or C 1 -C 6 alkyl, and the alkyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy, or both Rs 5 are cyclized together with the atom to which they are attached to form one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy-substituted C 3 -C 12 forms a cycloalkyl, R 6 is H, halo, -OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, and R 6’ is H, halo, -OH, C1 -C 6 alkyl, or C 1 -C 6 is alkoxy, and R 6” is H, halo, -OH, C 1 -C 6 alkyl, or C 1 -C 6 is alkoxy, and R 7 is independently H or C 1 -C 4 is alkyl, and n is an integer of 0, 1, 2, or 3, and p is an integer of 0, 1, or 2.

[0078] In some embodiments, each R 5 is independently fluoro or C 1 -C 6 alkyl, where the alkyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 is alkoxy, or both Rs 5 cyclize together with the atom to which they are attached to form one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 is optionally substituted with alkoxy to form C 3 -C 12 cycloalkyl.

[0079] In some embodiments, the compound of formula (I) is a compound of formula (I-A), [Chemical formula] or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, wherein R 1 is halo, -CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 -C 12 cycloalkyl, each R 2 and R 3 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, and alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C6 optionally substituted with alkoxy, or R 2 and R 3 together with the atom to which they are attached cyclize to form a C 3 -C 12 cycloalkyl or 3- to 12-membered heterocyclyl, where the cycloalkyl or heterocyclyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 optionally substituted with alkoxy, R 4 is -C 1 -C 6 alkyl, -(L 1 ) p -(C 3 -C 12 cycloalkyl)-, -(L 1 ) p -(3- to 12-membered heterocyclyl)-, -(L 1 ) p -(C 6 -C 10 aryl)-, or -(L 1 ) p -(5- to 10-membered heteroaryl)-, and each R L1 is independently H, halo, or C 1 -C 3 alkyl, or two R L1 groups together with the atom to which they are attached form a C 3 cycloalkyl, and the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C6 Haloalkyl, C 1 -C 6 Alkoxy, or C 3 Optionally substituted with cycloalkyl, Z is -(L 2 ) n -(Carboxylic acid) or -(L 2 ) n -Tetrazole, and each L 2 is independently -(C(R L2 ) 2 -, and furthermore, each R L2 is independently H, halo, or C 1 -C 3 Alkyl, or two R L2 groups together with the atom to which they are attached form C 3 Cycloalkyl, and the alkyl or cycloalkyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, or C 3 Optionally substituted with cycloalkyl, Each R 5 is independently fluoro or C 1 -C 6 Alkyl, and the alkyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 Optionally substituted with alkoxy, or both R 5which cyclize together with the atoms to which they are attached to form one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 optionally substituted with alkoxy C 3 -C 12 cycloalkyl, and R 6 is H, halo, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy, and R 6’ is H, halo, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy, and R 6” is H, halo, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy, and n is an integer of 0, 1, 2, or 3, p is an integer of 0, 1, or 2).

[0080] In some embodiments of formula (I-A), R 1 is bromo, chloro, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 12 cycloalkyl, each R 2 and R 3 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, where alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy, or R 2 and R 3 together cyclize to form C 3 -C 12 cycloalkyl or 3- to 12-membered heterocyclyl, where cycloalkyl or heterocyclyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C6 optionally substituted with alkoxy, R 4 is -(n-propyl)-, -(L 1 ) p -(C 3 -C 12 -cycloalkyl)-, -(L 1 ) p -(3- to 12-membered heterocyclyl), -(L 1 ) p -(C 6 -C 10 -aryl)-, or -(L 1 ) p -(5- to 10-membered heteroaryl)-, and each R L1 is independently H, halo, or C 1 -C 3 -alkyl, or two R L1 groups together with the atom to which they are attached form a C 3 -cycloalkyl, and n-propyl, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, or C 3 -cycloalkyl optionally substituted with alkoxy, Z is -(L 2 ) n -(carboxylic acid) or -(L 2 ) n -tetrazole, and each L 2 is independently -(C(R L2 ) 2 - and each R L2 is independently H, halo, or C 1 -C 3 -alkyl, or two R L2The base, together with the atoms to which they are attached, forms a C 3 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 cycloalkyl, and each R 5 is independently fluoro or C 1 -C 6 alkyl, and the alkyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy, or both Rs 5 cyclize with the atoms to which they are attached to form a C with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy optionally substituted C 3 -C 12 cycloalkyl, and R 6 is H, halo, -OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, and R 6’ is H, halo, -OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, and R 6” is H, halo, -OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, and n is an integer of 0, 1, 2, or 3, and p is an integer of 0, 1, or 2.

[0081] In this specification, additional embodiments are further envisioned.

[0082] (a) R 2 and R 3 groups As generally defined herein, each R 2 and R 3 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, and alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6Haloalkyl, or C 1 -C 6 optionally substituted with alkoxy, or R 2 and R 3 together with the atom to which they are attached cyclize to form a C 3 -C 12 cycloalkyl or 3- to 12-membered heterocyclyl, and the cycloalkyl or heterocyclyl is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 optionally substituted with alkoxy.

[0083] In some embodiments, each R 2 and R 3 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, and the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C1 -C 6 is optionally substituted with alkoxy.

[0084] In some embodiments, each R 2 and R 3 is independently H.

[0085] In some embodiments, each R 2 and R 3 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 is optionally substituted with alkoxy.

[0086] In some embodiments, R 2 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1-C 6 alkoxy, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, where alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy.

[0087] In some embodiments, R 2 is H.

[0088] In some embodiments, R 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, where alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C1 -C 6 Haloalkyl, or C 1 -C 6 is optionally substituted with alkoxy.

[0089] In some embodiments, R 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl.

[0090] In some embodiments, R 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy, and the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy.

[0091] In some embodiments, R 2 is C 1 -C6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 is alkoxy.

[0092] In some embodiments, R 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 is alkynyl.

[0093] In some embodiments, R 2 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with C 1 -C 6 is alkoxy.

[0094] In some embodiments, R 2 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl substituted with C 1 -C 6 is alkoxy.

[0095] In some embodiments, R 2 is C 1 -C 6 alkyl.

[0096] In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is propyl. In some embodiments, R 2 is butyl. In some embodiments, R 2 is pentyl. In some embodiments, R 2 is hexyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is isobutyl. In some embodiments, R 2 is isopentyl. In some embodiments, R 2 is isohexyl. In some embodiments, R 2 is sec-butyl. In some embodiments, R 2 is sec-pentyl. In some embodiments, R 2 is sec-hexyl. In some embodiments, R 2 is tert-butyl.

[0097] In some embodiments, R 2 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkenyl optionally substituted with C 2 -C 6 alkoxy.

[0098] In some embodiments, R 2is one or more halos, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 substituted with C 2 -C 6 alkenyl.

[0099] In some embodiments, R 2 is C 2 -C 6 alkenyl.

[0100] In some embodiments, R 2 is C 2 alkenyl. In some embodiments, R 2 is C 3 alkenyl. In some embodiments, R 2 is C 4 alkenyl. In some embodiments, R 2 is C 5 alkenyl. In some embodiments, R 2 is C 6 alkenyl.

[0101] In some embodiments, R 2 is one or more halos, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 optionally substituted with C 2 -C 6 alkynyl.

[0102] In some embodiments, R 2 is one or more halos, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkynyl substituted with C 2 -C 6 alkoxy.

[0103] In some embodiments, R 2 is C 2 -C 6 alkynyl.

[0104] In some embodiments, R 2 is C 2 alkynyl. In some embodiments, R 2 is C 3 alkynyl. In some embodiments, R 2 is C 4 alkynyl. In some embodiments, R 2 is C 5 alkynyl. In some embodiments, R 2 is C 6 alkynyl.

[0105] In some embodiments, R 2 is C 1 -C 6 haloalkyl or, C 1 -C 6 alkoxy.

[0106] In some embodiments, R 2 is one or more halos, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6Alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkyl optionally substituted with C 1 -C 6 is haloalkyl.

[0107] In some embodiments, R 2 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkyl substituted with C 1 -C 6 is haloalkyl.

[0108] In some embodiments, R 2 is C 1 -C 6 haloalkyl.

[0109] In some embodiments, R 2 is halomethyl. In some embodiments, R 2 is haloethyl. In some embodiments, R 2 is halopropyl. In some embodiments, R 2 is halobutyl. In some embodiments, R 2 is halopentyl. In some embodiments, R 2 is halohexyl.

[0110] In some embodiments, R 2 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 Optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 Is alkoxy.

[0111] In some embodiments, R 2 Is one or more halo, -CN, -OH, amino, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 Substituted with alkoxy C 1 -C 6 Is alkoxy.

[0112] In some embodiments, R 2 Is C 1 -C 6 Is alkoxy.

[0113] In some embodiments, R 2 Is methoxy. In some embodiments, R 2 Is ethoxy. In some embodiments, R 2 Is propoxy. In some embodiments, R 2 Is butoxy. In some embodiments, R 2 Is pentoxy. In some embodiments, R 2 Is hexyloxy.

[0114] In some embodiments, R 2 Is C 3 -C 12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 10Aryl, or 5- to 10-membered heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy.

[0115] In some embodiments, R 2 is C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl.

[0116] In some embodiments, R 2 is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy-substituted C 3 -C 12 cycloalkyl.

[0117] In some embodiments, R 2 is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C6 C substituted with alkoxy 3 -C 12 is cycloalkyl.

[0118] In some embodiments, R 2 is C 3 -C 12 is cycloalkyl.

[0119] In some embodiments, R 2 is C 3 -C 6 is cycloalkyl.

[0120] In some embodiments, R 2 is C 3 is cycloalkyl. In some embodiments, R 2 is C 4 is cycloalkyl. In some embodiments, R 2 is C 5 is cycloalkyl. In some embodiments, R 2 is C 6 is cycloalkyl.

[0121] In some embodiments, R 2 is C 7 is cycloalkyl. In some embodiments, R 2 is C 8 is cycloalkyl. In some embodiments, R 2 is C 9 is cycloalkyl. In some embodiments, R 2 is C 10 is cycloalkyl. In some embodiments, R 2 is C 11 is cycloalkyl. In some embodiments, R 2 is C 12 is cycloalkyl.

[0122] In some embodiments, R 2 is one or more halo, -CN, -OH, amino, C 1 -C 6Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 is a 3- to 12-membered heterocyclyl optionally substituted with alkoxy.

[0123] In some embodiments, R 2 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 is a 3- to 12-membered heterocyclyl substituted with alkoxy.

[0124] In some embodiments, R 2 is a 3- to 12-membered heterocyclyl.

[0125] In some embodiments, R 2 is a 3-membered heterocyclyl. In some embodiments, R 2 is a 4-membered heterocyclyl. In some embodiments, R 2 is a 5-membered heterocyclyl. In some embodiments, R 2 is a 6-membered heterocyclyl. In some embodiments, R 2 is a 7-membered heterocyclyl. In some embodiments, R 2 is an 8-membered heterocyclyl. In some embodiments, R 2 is a 9-membered heterocyclyl. In some embodiments, R 2 is a 10-membered heterocyclyl. In some embodiments, R 2 is an 11-membered heterocyclyl. In some embodiments, R 2 is a 12-membered heterocyclyl.

[0126] In some embodiments, R 2 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 aryl optionally substituted with C 6 -C 10 alkoxy.

[0127] In some embodiments, R 2 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 aryl substituted with C 6 -C 10 alkoxy.

[0128] In some embodiments, R 2 is C 6 -C 10 aryl.

[0129] In some embodiments, R 2 is C 6 aryl. In some embodiments, R 2 is C 8 aryl. In some embodiments, R 2 is C 10 aryl.

[0130] In some embodiments, R 2 is one or more halo, -CN, -OH, amino, C1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 is a 5- to 10-membered heteroaryl optionally substituted with alkoxy.

[0131] In some embodiments, R 2 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 is a 5- to 10-membered heteroaryl substituted with alkoxy.

[0132] In some embodiments, R 2 is a 5- to 10-membered heteroaryl.

[0133] In some embodiments, R 2 is a 5-membered heteroaryl. In some embodiments, R 2 is a 6-membered heteroaryl. In some embodiments, R 2 is a 7-membered heteroaryl. In some embodiments, R 2 is an 8-membered heteroaryl. In some embodiments, R 2 is a 9-membered heteroaryl. In some embodiments, R 2 is a 10-membered heteroaryl.

[0134] In some embodiments, R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy.

[0135] In some embodiments, R 3 is H.

[0136] In some embodiments, R 3 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 is optionally substituted with alkoxy.

[0137] In some embodiments, R 3 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl.

[0138] In some embodiments, R 3 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 is alkoxy, and alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6It is optionally substituted with alkoxy.

[0139] In some embodiments, R 3 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 is alkoxy.

[0140] In some embodiments, R 3 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 is alkynyl.

[0141] In some embodiments, R 3 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with alkoxy and C 1 -C 6 is alkyl.

[0142] In some embodiments, R 3 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C6 C substituted with alkoxy 1 -C 6 is alkyl.

[0143] In some embodiments, R 3 is C 1 -C 6 is alkyl.

[0144] In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is propyl. In some embodiments, R 3 is butyl. In some embodiments, R 3 is pentyl. In some embodiments, R 3 is hexyl. In some embodiments, R 3 is isopropyl. In some embodiments, R 3 is isobutyl. In some embodiments, R 3 is isopentyl. In some embodiments, R 3 is isohexyl. In some embodiments, R 3 is sec-butyl. In some embodiments, R 3 is sec-pentyl. In some embodiments, R 3 is sec-hexyl. In some embodiments, R 3 is tert-butyl.

[0145] In some embodiments, R 3 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 C optionally substituted with alkoxy2 -C 6 is alkenyl.

[0146] In some embodiments, R 3 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkenyl substituted with C 2 -C 6 is alkoxy.

[0147] In some embodiments, R 3 is C 2 -C 6 is alkenyl.

[0148] In some embodiments, R 3 is C 2 is alkenyl. In some embodiments, R 3 is C 3 is alkenyl. In some embodiments, R 3 is C 4 is alkenyl. In some embodiments, R 3 is C 5 is alkenyl. In some embodiments, R 3 is C 6 is alkenyl.

[0149] In some embodiments, R 3 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6C optionally substituted with alkoxy 2 -C 6 is alkynyl.

[0150] In some embodiments, R 3 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkynyl substituted with alkoxy. 2 -C 6 is alkynyl.

[0151] In some embodiments, R 3 is C 2 -C 6 alkynyl.

[0152] In some embodiments, R 3 is C 2 alkynyl. In some embodiments, R 3 is C 3 alkynyl. In some embodiments, R 3 is C 4 alkynyl. In some embodiments, R 3 is C 5 alkynyl. In some embodiments, R 3 is C 6 alkynyl.

[0153] In some embodiments, R 3 is C 1 -C 6 haloalkyl or, C 1 -C 6 is alkoxy.

[0154] In some embodiments, R 3 is one or more halo, -CN, -OH, amino, C1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 C optionally substituted with alkoxy 1 -C 6 is haloalkyl.

[0155] In some embodiments, R 3 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 C substituted with alkoxy 1 -C 6 is haloalkyl.

[0156] In some embodiments, R 3 is C 1 -C 6 is haloalkyl.

[0157] In some embodiments, R 3 is halomethyl. In some embodiments, R 3 is haloethyl. In some embodiments, R 3 is halopropyl. In some embodiments, R 3 is halobutyl. In some embodiments, R 3 is halopentyl. In some embodiments, R 3 is halohexyl.

[0158] In some embodiments, R 3 is one or more halo, -CN, -OH, amino, C1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 C optionally substituted with alkoxy 1 -C 6 is alkoxy.

[0159] In some embodiments, R 3 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 C substituted with alkoxy 1 -C 6 is alkoxy.

[0160] In some embodiments, R 3 is C 1 -C 6 is alkoxy.

[0161] In some embodiments, R 3 is methoxy. In some embodiments, R 3 is ethoxy. In some embodiments, R 3 is propoxy. In some embodiments, R 3 is butoxy. In some embodiments, R 3 is pentyloxy. In some embodiments, R 3 is hexyloxy.

[0162] In some embodiments, R 3 is C 3 -C 12Cycloalkyl, 3- to 12-membered heterocyclyl, C 6 -C 10 Aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 Alkoxy.

[0163] In some embodiments, R 3 is C 3 -C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, C 6 -C 10 Aryl, or 5- to 10-membered heteroaryl.

[0164] In some embodiments, R 3 is one or more halo, -CN, -OH, amino, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 Alkoxy-substituted C 3 -C 12 Cycloalkyl.

[0165] In some embodiments, R 3 is one or more halo, -CN, -OH, amino, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C1 -C 6 haloalkyl, or C 1 -C 6 substituted with alkoxy C 3 -C 12 is cycloalkyl.

[0166] In some embodiments, R 3 is C 3 -C 12 is cycloalkyl.

[0167] In some embodiments, R 3 is C 3 -C 6 is cycloalkyl.

[0168] In some embodiments, R 3 is C 3 is cycloalkyl. In some embodiments, R 3 is C 4 is cycloalkyl. In some embodiments, R 3 is C 5 is cycloalkyl. In some embodiments, R 3 is C 6 is cycloalkyl.

[0169] In some embodiments, R 3 is C 7 is cycloalkyl. In some embodiments, R 3 is C 8 is cycloalkyl. In some embodiments, R 3 is C 9 is cycloalkyl. In some embodiments, R 3 is C 10 is cycloalkyl. In some embodiments, R 3 is C 11 is cycloalkyl. In some embodiments, R 3 is C 12 is cycloalkyl.

[0170] In some embodiments, R3 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 is a 3- to 12-membered heterocyclyl optionally substituted with alkoxy.

[0171] In some embodiments, R 3 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 is a 3- to 12-membered heterocyclyl substituted with alkoxy.

[0172] In some embodiments, R 3 is a 3- to 12-membered heterocyclyl.

[0173] In some embodiments, R 3 is a 3-membered heterocyclyl. In some embodiments, R 3 is a 4-membered heterocyclyl. In some embodiments, R 3 is a 5-membered heterocyclyl. In some embodiments, R 3 is a 6-membered heterocyclyl. In some embodiments, R 3 is a 7-membered heterocyclyl. In some embodiments, R 3 is an 8-membered heterocyclyl. In some embodiments, R 3 is a 9-membered heterocyclyl. In some embodiments, R 3 is a 10-membered heterocyclyl. In some embodiments, R 3is an 11-membered heterocycle. In some embodiments, R 3 is a 12-membered heterocycle.

[0174] In some embodiments, R 3 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 aryl optionally substituted with C 6 -C 10 alkoxy.

[0175] In some embodiments, R 3 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 aryl substituted with C 6 -C 10 alkoxy.

[0176] In some embodiments, R 3 is C 6 -C 10 aryl.

[0177] In some embodiments, R 3 is C 6 aryl. In some embodiments, R 3 is C 8 aryl. In some embodiments, R 3 is C 10 aryl.

[0178] In some embodiments, R 3 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 is a 5- to 10-membered heteroaryl optionally substituted with alkoxy.

[0179] In some embodiments, R 3 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 is a 5- to 10-membered heteroaryl substituted with alkoxy.

[0180] In some embodiments, R 3 is a 5- to 10-membered heteroaryl.

[0181] In some embodiments, R 3 is a 5-membered heteroaryl. In some embodiments, R 3 is a 6-membered heteroaryl. In some embodiments, R 3 is a 7-membered heteroaryl. In some embodiments, R 3 is an 8-membered heteroaryl. In some embodiments, R 3 is a 9-membered heteroaryl. In some embodiments, R 3 is a 10-membered heteroaryl.

[0182] In some embodiments, R 2 and R 3cyclize together with the atoms to which they are attached to form a C 3 -C 12 cycloalkyl or 3- to 12-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 optionally substituted with alkoxy.

[0183] In some embodiments, R 2 and R 3 cyclize together with the atoms to which they are attached to form a C 1 -C 6 cycloalkyl optionally substituted with one or more halo, -CN, -OH, amino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 optionally substituted with alkoxy to form a C 3 -C 12 cycloalkyl.

[0184] In some embodiments, R 2 and R 3 cyclize together with the atoms to which they are attached to form a C 1 -C 6 cycloalkyl optionally substituted with one or more halo, -CN, -OH, amino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 optionally substituted with alkoxy to form a C 3 -C12 Form a cycloalkyl.

[0185] In some embodiments, R 2 and R 3 cyclize together with the atoms to which they are attached to form a C 3 -C 12 Form a cycloalkyl.

[0186] In some embodiments, R 2 and R 3 cyclize together with the atoms to which they are attached to form a C 3 Form a cycloalkyl. In some embodiments, R 2 and R 3 cyclize together with the atoms to which they are attached to form a C 4 Form a cycloalkyl. In some embodiments, R 2 and R 3 cyclize together with the atoms to which they are attached to form a C 5 Form a cycloalkyl. In some embodiments, R 2 and R 3 cyclize together with the atoms to which they are attached to form a C 6 Form a cycloalkyl. In some embodiments, R 2 and R 3 cyclize together with the atoms to which they are attached to form a C 7 Form a cycloalkyl. In some embodiments, R 2 and R 3 cyclize together with the atoms to which they are attached to form a C 8 Form a cycloalkyl. In some embodiments, R 2 and R 3 cyclize together with the atoms to which they are attached to form a C 9 Form a cycloalkyl. In some embodiments, R 2 and R 3 cyclize together with the atoms to which they are attached to form a C 10 Form a cycloalkyl. In some embodiments, R 2 and R 3cyclize with the atoms to which they are attached to form a C 11 cycloalkyl. In some embodiments, R 2 and R 3 cyclize with the atoms to which they are attached to form a C 12 cycloalkyl.

[0187] In some embodiments, R 2 and R 3 cyclize with the atoms to which they are attached to form a cycloalkyl optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 cycloalkyl optionally substituted with C 3 alkoxy.

[0188] In some embodiments, R 2 and R 3 cyclize with the atoms to which they are attached to form a cycloalkyl optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 cycloalkyl optionally substituted with C 3 alkoxy.

[0189] In some embodiments, R 2 and R 3 cyclize with the atoms to which they are attached to form a cycloalkyl optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 forms a 3- to 12-membered heterocyclyl optionally substituted with alkoxy.

[0190] In some embodiments, R 2 and R 3 cyclize together with the atoms to which they are attached to form one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 forms a 3- to 12-membered heterocyclyl optionally substituted with alkoxy.

[0191] In some embodiments, R 2 and R 3 cyclize together with the atoms to which they are attached to form a 3- to 12-membered heterocyclyl.

[0192] In some embodiments, R 2 and R 3 cyclize together with the atoms to which they are attached to form a 3-membered heterocyclyl. In some embodiments, R 2 and R 3 cyclize together with the atoms to which they are attached to form a 4-membered heterocyclyl. In some embodiments, R 2 and R 3 cyclize together with the atoms to which they are attached to form a 5-membered heterocyclyl. In some embodiments, R 2 and R 3 cyclize together with the atoms to which they are attached to form a 6-membered heterocyclyl. In some embodiments, R 2 and R3 cyclize with the atoms to which they are attached to form a 7-membered heterocyclyl. In some embodiments, R 2 and R 3 cyclize with the atoms to which they are attached to form an 8-membered heterocyclyl. In some embodiments, R 2 and R 3 cyclize with the atoms to which they are attached to form a 9-membered heterocyclyl. In some embodiments, R 2 and R 3 cyclize with the atoms to which they are attached to form a 10-membered heterocyclyl. In some embodiments, R 2 and R 3 cyclize with the atoms to which they are attached to form an 11-membered heterocyclyl. In some embodiments, R 2 and R 3 cyclize with the atoms to which they are attached to form a 12-membered heterocyclyl.

[0193] In some embodiments, each R 2 and R 3 is independently H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or R 2 and R 3 cyclize with the atoms to which they are attached to form C 3 cycloalkyl. In some embodiments, each R 2 and R 3 is H. In some embodiments, R 2 and R 3 cyclize with the atoms to which they are attached to form C 3 cycloalkyl.

[0194] (b) L 1 、L 2 、R 4 、R 7 groups, Z, p, and n As generally defined herein, R4 is -C 1 -C 6 -alkyl-, -(L 1 ) p -(C 3 -C 12 -cycloalkyl)-, -(L 1 ) p -(3- to 12-membered heterocyclyl)-, -(L 1 ) p -(C 6 -C 10 -aryl)-, or -(L 1 ) p -(5- to 10-membered heteroaryl)-, and each L 1 is independently -(C(R L1 ) 2 )-, and further each R L1 is independently H, halo, or C 1 -C 3 -alkyl, or two R L1 groups together with the atom to which they are attached form a C 3-4 -cycloalkyl, and alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, or C 3 -cycloalkyl, and p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0195] As further generally defined herein, Z is -(L 2 ) n -(carboxylic acid) or -(L 2 ) n -tetrazole, and each L2 is, independently, -(C(R L2 )) 2 -, and further, each R L2 is, independently, H, halo, or C 1 -C 3 alkyl, or two R L2 groups, together with the atom to which they are attached, form C 3 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 cycloalkyl, and n is 0, 1, 2, or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0196] As further generally defined herein, R 7 is, independently, H or C 1 -C 4 alkyl. In some embodiments, R 7 is H. In some embodiments, R 7 is C 1 -C 4 alkyl. In some embodiments, R 7 is methyl. In some embodiments, R 7 is ethyl. In some embodiments, R 7 is propyl. In some embodiments, R 7 is isopropyl. In some embodiments, R 7 is n-butyl. In some embodiments, R 7 is sec-butyl. In some embodiments, R7 is tert-butyl.

[0197] In some embodiments, R 7 is H or methyl.

[0198] R 4 is understood to be a divalent moiety having two attachment points, one attachment point to the amide nitrogen and the other attachment point to the Z moiety. The groups recited herein are read from left to right, with the leftmost recitation being attached to the NR 7 amide nitrogen and the rightmost recitation being attached to Z. For example, for the groups -(L 7 ) 1 -(C p -C 3 -cycloalkyl)-, -(L 12 ) 1 -(3- to 12-membered heterocyclyl)-, and -(L p ) 1 -(5- to 10-membered heteroaryl)-, the leftmost -(L p ) 1 - group is attached to the NR p amide nitrogen. It is further understood that a portion of the Z group, namely -(L 7 ) 2 -(wherein n is 0, 1, 2, or 3) also includes part of a linker that joins the NR n amide nitrogen to the terminal carboxylic acid or tetrazole group. 7

[0199] In some embodiments where each L 1 is independently -(C(R L1 ) 2 )-, at least one instance of R 1 is -C p -C L1 alkyl optionally substituted with one or more halos. In some embodiments, at least one instance of R 1 is H. In some embodiments, each R 3 is H, i.e., each L L1 is -(CH L1 1 -2 ) - is.

[0200] In the formula, each L 2 is independently - (C(R L2 )) 2 ) - of - (L 2 ) n - In some embodiments of, at least one example of R L2 is optionally substituted with one or more halos - C 1 - C 3 is alkyl. In some embodiments, at least two examples of R L2 are H. In some embodiments, each R L2 is H, that is, each L 1 is - (CH 2 ) -.

[0201] In some embodiments, each L 1 is - (CH 2 ) -, and each L 2 is - (CH 2 ) -. In some embodiments, p is 1, and L 1 is - (CH(CH 3 )) -, and each L 2 is - (CH 2 ) -.

[0202] In some embodiments, R 4 is - C 1 - C 6 alkyl -, - (CH 2 ) p - (C 3 - C 12 cycloalkyl) -, - (3 - 12 membered heterocyclyl) -, - C 6 - C 10 aryl -, or - (CH 2 ) p - (5 - 10 membered heteroaryl) -, and alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more halos, - CN, - OH, amino, C 1 - C 6 alkyl, C2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 is optionally substituted with alkoxy. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0203] In some embodiments, R 4 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl - optionally substituted with alkoxy -C 1 -C 6 alkyl-.

[0204] In some embodiments, R 4 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl - substituted with alkoxy -C 1 -C 6 alkyl-.

[0205] In some embodiments, R 4 is -(CH 2 ) p -(C 3 -C 12 cycloalkyl)-, -(3 - 12 membered heterocyclyl)-, -C6 -C 10 -aryl, or -(CH 2 ) p -(5- to 10-membered heteroaryl)-, wherein cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -haloalkyl, or C 1 -C 6 -alkoxy. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0206] In some embodiments, R 4 is -(CH 2 ) p -(C 3 -C 12 -cycloalkyl)-. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0207] In some embodiments, R 4 is -(CH 2 ) p -(C 3 -C 12 -cycloalkyl)-, wherein cycloalkyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -haloalkyl, or C 1 -C 6Optionally substituted with alkoxy. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0208] In some embodiments, R 4 is -(CH 2 ) p -(3- to 12-membered heterocyclyl)-. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0209] In some embodiments, R 4 is -(CH 2 ) p -(3- to 12-membered heterocyclyl)-, and the heterocyclyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 optionally substituted with alkoxy. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0210] In some embodiments, R 4 is -(3- to 12-membered heterocyclyl)-.

[0211] In some embodiments, R 4 is -(3- to 12-membered heterocyclyl)-, and the heterocyclyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C1 -C 6 Optionally substituted with alkoxy.

[0212] In some embodiments, R 4 is -C 6 -C 10 aryl-.

[0213] In some embodiments, R 4 is -C 6 -C 10 aryl-, and the aryl is one or more of halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 Optionally substituted with alkoxy.

[0214] In some embodiments, R 4 is -C 6 aryl-.

[0215] In some embodiments, R 4 is -C 6 aryl-, and the aryl is one or more of halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 Optionally substituted with alkoxy.

[0216] In some embodiments, R 4 is -(CH 2 ) p-(5 to 10-membered heteroaryl)-. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0217] In some embodiments, R 4 is -(CH 2 ) p -(5 to 10-membered heteroaryl)-, and the heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0218] In some embodiments, R 4 is -(CH 2 ) p -(6-membered heteroaryl)-. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0219] In some embodiments, R 4 is -(CH 2 ) p -(6-membered heteroaryl)-, and the heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6Optionally substituted with alkoxy. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0220] In some embodiments, R 4 is -(n-propyl)-, -(CH 2 ) p -(C 3 -C 12 cycloalkyl)-, -(3- to 12-membered heterocyclyl)-, -C 6 -C 10 aryl-, or -(CH 2 ) p -(5- to 10-membered heteroaryl)-, where n-propyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 optionally substituted with alkoxy. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0221] In some embodiments, R 4 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 optionally substituted with alkoxy and is -(n-propyl)-.

[0222] In some embodiments, R 4is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 substituted with alkoxy is -(n-propyl)-.

[0223] In some embodiments, R 4 is -(n-propyl)-.

[0224] In some embodiments, Z is -(CH 2 ) n -(carboxylic acid) or tetrazole. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0225] In some embodiments, Z is -(CH 2 ) n -(carboxylic acid). In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0226] In some embodiments, n is 0 and Z is carboxylic acid.

[0227] In some embodiments, Z is -(CH 2 ) n -tetrazole. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0228] In some embodiments, n is 0 and Z is tetrazole.

[0229] As described herein, the combination of R 4 is a divalent moiety, and the - (L 2 ) n - of the Z group forms a linker group that joins the amide nitrogen to the terminal carboxylic acid or tetrazole group. In some embodiments, the minimum number of consecutive covalent bond atoms between the NR 7 amide nitrogen and the terminal carboxylic acid or tetrazole group is three consecutive covalent bond atoms. 7

[0230] In some embodiments, R 4 is - (L 1 ) p - (C 3 -C 12 cycloalkyl)- or - (L 1 ) p - (3 - to 12 - membered heterocyclyl)-, where the cycloalkyl or heterocyclyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 cycloalkyl, p is 0, n is 2, Z is - (L 2 ) n - (carboxylic acid) or - (L 2 ) n - tetrazole, and the minimum number of consecutive covalent bond atoms between the NR 7 amide nitrogen and the terminal carboxyl acid or tetrazole group is three consecutive covalent bond atoms. For example, in some embodiments, -R 4- Z is a group of formula (i):

Chemical formula

[0231] In some embodiments, the group of formula (i) is

Chemical formula

[0232] In some embodiments, the group of formula (i) is

Chemical formula

[0233] In some embodiments, R 4 is -(L 1 ) p -(C 3 -C 12 cycloalkyl)- or -(L 1 ) p -(3- to 12-membered heterocyclyl)-, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C6 Haloalkyl, C 1 -C 6 Alkoxy, or C 3 Cycloalkyl optionally substituted, p is 1, n is 1, Z is -(L 2 ) n -(Carboxylic acid) or -(L 2 ) n -Tetrazole, and the minimum number of consecutive shared bond atoms between the amide nitrogen and the terminal carboxylic acid or tetrazole group is 3 consecutive shared bond atoms. For example, in some embodiments, -R 7 Z is a group of formula (ii): 4-

Chemical formula

[0234] In some embodiments, the group of formula (ii) is [Chemical formula] (wherein Z’ is tetrazole or carboxylic acid).

[0235] In some embodiments, the group of formula (ii-a) is [Chemical formula] is.

[0236] In some embodiments, R 4 is -(L 1 ) p -(C 3 -C 12 cycloalkyl)-, -(L 1 ) p -(3- to 12-membered heterocyclyl)-, -(L 2 ) p -(C 6 -C 10 aryl)-, or -(L 2 ) p -(5- to 10-membered heteroaryl)-, and cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 cycloalkyl, p is 0, n is 0, Z is -(L 2 ) n -(carboxylic acid) or -(L 2 ) n -tetrazole, and the minimum number of consecutive shared bond atoms between the amide nitrogen and the terminal carboxylic acid or tetrazole group is 3 consecutive shared bond atoms. For example, in some embodiments, -R 7 is 4-Z is a group of formula (iii): [Chemical formula] (wherein Z’ is tetrazole or carboxylic acid, ring A is C 3 -C 5 cycloalkyl or 4- to 5-membered heterocyclyl, each R 4a is independently halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 cycloalkyl, and x is 0, 1, 2, or 3).

[0237] In some embodiments, the group of formula (iii) is [Chemical formula] (wherein Z’ is tetrazole or carboxylic acid).

[0238] In some embodiments, the group of formula (iii-a) is [Chemical formula] as follows.

[0239] In some embodiments, R 4 is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 cycloalkyl optionally substituted -(n-propyl)-, n is 0, and Z is -(L 2 ) n -(carboxylic acid) or -(L 2 ) n-tetrazole, NR 7 The number of consecutive covalent bond atoms between the amide nitrogen and the terminal carboxylic acid or tetrazole group is 3 consecutive covalent bond atoms. In some embodiments, R 4 is independently 0, 1, 2, or 3 halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 cycloalkyl-substituted -(n-propyl)-, where n is 0 and Z is -(L 2 ) n -(carboxylic acid) or -(L 2 ) n -tetrazole. In some embodiments, R 4 is independently 0, 1, 2, or 3 fluoro, -CH 3 , -CF 3 , or C 3 cycloalkyl-substituted -(n-propyl)-, where n is 0 and Z is -(L 2 ) n -(carboxylic acid) or -(L 2 ) n -tetrazole. In some embodiments, -RZ 4- is a group of formula (iv):

Chemical formula

[0240] In some embodiments, the group of formula (iv) is of the formula: [Chemical Formula] (wherein Z’ is tetrazole or carboxylic acid, and each R 4a is independently halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 cycloalkyl). In some embodiments, each R 4a is independently -CH 3 , -CF 3 , C 3 cycloalkyl, or fluoro.

[0241] In some embodiments, the group of formula (iv) is of the formula: [Chemical Formula] (wherein Z’ is tetrazole or carboxylic acid, and each R 4a is independently halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 cycloalkyl). In some embodiments, each R 4a is independently -CH 3 , -CF 3 , C 3 cycloalkyl, or fluoro.

[0242] In some embodiments, the group of formula (iv) is of the formula: [Chemical Formula] [Chemical Formula] is of the following.

[0243] In some embodiments, p is 1, n is 0, and Z is -(L 2 ) n -(carboxylic acid) or -(L 2 ) n -tetrazole, and R 4 is -(L 1 ) p -(C 6 -C 10 aryl)- or -(L 1 ) p -(5- to 10-membered heteroaryl), where the aryl or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 cycloalkyl, and the minimum number of consecutive shared bond atoms between the NR 7 amide nitrogen and the terminal carboxylic acid or tetrazole group is 3 consecutive shared bond atoms. In some embodiments, provided is an -R 4- Z group of formula (v):

Chemical formula

[0244] In some embodiments, R of formula (v-a) 4- The Z group is

Chemical formula

[0245] In some embodiments, the minimum number of consecutive shared bond atoms between the amide nitrogen and the terminal carboxylic acid or tetrazole group is two consecutive shared bond atoms. For example, in some embodiments, p is 0, n is 0, Z is -(L 7 ) 2 -(carboxylic acid) or -(L n ) 2 -tetrazole, and R n is -(L 4 ) 1 -(C p -C 3 -cycloalkyl)-, -(L 12 ) 1 -(3- to 12-membered heterocyclyl)-, -(L p ) 1 -(C p -C 6 -aryl)-, or -(L 10 ) 1 -(5- to 10-membered heteroaryl), where cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C p -C 1 -alkyl, C 6 -C 2 -alkenyl, C 6 -C 2 -alkynyl, C 6 -C 1 -haloalkyl, C 6 -C 1 -alkoxy, or C 6 -cycloalkyl, and the minimum number of consecutive shared bond atoms between the amide nitrogen of NR 3 and the terminal carboxylic acid or tetrazole group is two consecutive shared bond atoms. In some embodiments, provided is the -R 7 Z group of formula (vi): 4- ​ [Chemical formula] (wherein Z’ is tetrazole or carboxylic acid, each R 4a is independently halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and x is 0, 1, 2, or 3).

[0246] In some embodiments, the R 4- Z group of formula (vi) is [Chemical formula] is.

[0247] In some embodiments, the minimum number of consecutive covalent bond atoms between the amide nitrogen and the terminal carboxylic acid or tetrazole group is 4 consecutive covalent bond atoms (e.g., carbon atoms). For example, in some embodiments, p is 0, n is 0, Z is -(L 7 ) 2 -(carboxylic acid) or -(L n ) 2 -tetrazole, and R n is -(L 4 ) 1 ) p -(C 6 -C 10 aryl)- or -(L 1 ) p -(5- to 10-membered heteroaryl)-, and the aryl or heteroaryl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 cycloalkyl, and NR 7The minimum number of consecutive covalently bonded atoms between the amide nitrogen and the terminal carboxylic acid or tetrazole group is four consecutive covalently bonded atoms. In some embodiments, provided is -R of formula (vii) 4- Z group:

Chemical formula

[0248] In some embodiments, the R 4- Z group of formula (vii) is

Chemical formula

[0249] (c) R 1 , R 5 , R 6 , R 6’ , R 6’‘ groups As generally defined herein, each R 5 is independently fluoro or C 1 -C 6 alkyl, and the alkyl is optionally substituted with one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy, or both R 5 cyclize together with the atom to which they are attached to form one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 C optionally substituted with alkoxy 3 -C 12 forms cycloalkyl.

[0250] In some embodiments, each R 5 is the same group. In some embodiments, each R 5 is halo. For example, in some embodiments, each R 5 is fluoro. In some embodiments, each R 5 is the same optionally substituted C 1 -C 6 alkyl group, for example, -CH 3 In some embodiments, each R 5 is different.

[0251] In some embodiments, each R 5 is independently C 1 -C 6 alkyl, and the alkyl is one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 optionally substituted with alkoxy.

[0252] In some embodiments, each R 5 is independently C 1 -C 6 alkyl, and the alkyl is one or more halo, -CN, -OH, amino, C 1 -C 6Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 is substituted with an alkoxy.

[0253] In some embodiments, each R 5 is, independently, C 1 -C 6 alkyl.

[0254] In some embodiments, at least one instance of R 5 is methyl. In some embodiments, at least one instance of R 5 is ethyl. In some embodiments, at least one instance of R 5 is propyl. In some embodiments, at least one instance of R 5 is butyl. In some embodiments, at least one instance of R 5 is pentyl. In some embodiments, at least one instance of R 5 is hexyl. In some embodiments, at least one instance of R 5 is isopropyl. In some embodiments, at least one instance of R 5 is isobutyl. In some embodiments, at least one instance of R 5 is isopentyl. In some embodiments, at least one instance of R 5 is isohexyl. In some embodiments, at least one instance of R 5 is sec-butyl. In some embodiments, at least one instance of R 5 is sec-pentyl. In some embodiments, at least one instance of R 5 is sec-hexyl. In some embodiments, at least one instance of R 5 is tert-butyl.

[0255] In some embodiments, both Rs 5 cyclize with the atoms to which they are attached to form one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 cycloalkyl optionally substituted with C 3 -C 12 alkoxy.

[0256] In some embodiments, both Rs 5 cyclize with the atoms to which they are attached to form one or more halo, -CN, -OH, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 cycloalkyl optionally substituted with C 3 -C 12 alkoxy.

[0257] In some embodiments, both Rs 5 cyclize with the atoms to which they are attached to form C 3 -C 12 cycloalkyl.

[0258] In some embodiments, both Rs 5 cyclize with the atoms to which they are attached to form C 3 cycloalkyl. In some embodiments, both Rs 5 cyclize with the atoms to which they are attached to form C 4 cycloalkyl. In some embodiments, both Rs5 cyclize with the atoms to which they are attached to form a C 5 cycloalkyl. In some embodiments, both Rs 5 cyclize with the atoms to which they are attached to form a C 6 cycloalkyl. In some embodiments, both Rs 5 cyclize with the atoms to which they are attached to form a C 7 cycloalkyl. In some embodiments, both Rs 5 cyclize with the atoms to which they are attached to form a C 8 cycloalkyl. In some embodiments, both Rs 5 cyclize with the atoms to which they are attached to form a C 9 cycloalkyl. In some embodiments, both Rs 5 cyclize with the atoms to which they are attached to form a C 10 cycloalkyl. In some embodiments, both Rs 5 cyclize with the atoms to which they are attached to form a C 11 cycloalkyl. In some embodiments, both Rs 5 cyclize with the atoms to which they are attached to form a C 12 cycloalkyl.

[0259] In some embodiments, each R 5 is selected from the group consisting of fluoro and C 1 -C 6 alkyl, or both Rs 5 cyclize with the atoms to which they are attached to form a C 3 cycloalkyl.

[0260] In some embodiments, each R 5 is selected from the group consisting of fluoro and C 1 -C 6 alkyl, or both Rs 5 cyclize with the atoms to which they are attached to form a C 3 or C5 Forms a cycloalkyl.

[0261] In some embodiments, each R 5 is the same and is selected from the group consisting of fluoro and C 1 -C 6 alkyl, or both Rs 5 cyclize with the atom to which they are attached to form a C 3 or C 5 cycloalkyl. In some embodiments, each R 5 is the same and is selected from the group consisting of fluoro and -CH 3 and, or both Rs 5 cyclize with the atom to which they are attached to form a C 3 or C 5 cycloalkyl. In some embodiments, each R 5 is fluoro. In some embodiments, each R 5 is -CH 3 In some embodiments, both Rs 5 cyclize with the atom to which they are attached to form a C 3 or C 5 cycloalkyl.

[0262] In some embodiments, each R 5 is the same and is selected from the group consisting of fluoro and C 1 -C 6 alkyl, or both Rs 5 cyclize with the atom to which they are attached to form a C 3 cycloalkyl. In some embodiments, each R 5 is the same and is selected from the group consisting of fluoro and -CH 3 and, or both Rs 5 cyclize with the atom to which they are attached to form a C 3 cycloalkyl. In some embodiments, each R 5is fluoro. In some embodiments, each R 5 is -CH 3 . In some embodiments, both Rs 5 cyclize with the atom to which they are attached to form a C 3 cycloalkyl.

[0263] As generally defined herein, R 1 is halo, -CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 -C 12 cycloalkyl.

[0264] In some embodiments, R 1 is halo or -CN.

[0265] In some embodiments, R 1 is halo. In some embodiments, R 1 is F, Br, Cl, or I. In some embodiments, R 1 is F, Br, or Cl. In some embodiments, R 1 is F. In some embodiments, R 1 is Br. In some embodiments, R 1 is Cl. In some embodiments, R 1 is I.

[0266] In some embodiments, R 1 is -CN.

[0267] In some embodiments, R 1 is C 1 -C 6 alkyl, C 2-C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, or C 3 -C 12 Is cycloalkyl.

[0268] In some embodiments, R 1 is C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, or C 2 -C 6 Is alkynyl.

[0269] In some embodiments, R 1 is C 1 -C 6 Is alkyl.

[0270] In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is propyl. In some embodiments, R 1 is butyl. In some embodiments, R 1 is pentyl. In some embodiments, R 1 is hexyl. In some embodiments, R 1 is isopropyl. In some embodiments, R 1 is isobutyl. In some embodiments, R 1 is isopentyl. In some embodiments, R 1 is isohexyl. In some embodiments, R 1 is sec-butyl. In some embodiments, R 1 is sec-pentyl. In some embodiments, R 1 is sec-hexyl. In some embodiments, R 1is tert-butyl.

[0271] In some embodiments, R 1 is C 2 -C 6 alkenyl.

[0272] In some embodiments, R 1 is C 2 alkenyl. In some embodiments, R 1 is C 3 alkenyl. In some embodiments, R 1 is C 4 alkenyl. In some embodiments, R 1 is C 5 alkenyl. In some embodiments, R 1 is C 6 alkenyl.

[0273] In some embodiments, R 1 is C 2 -C 6 alkynyl.

[0274] In some embodiments, R 1 is C 2 alkynyl. In some embodiments, R 1 is C 3 alkynyl. In some embodiments, R 1 is C 4 alkynyl. In some embodiments, R 1 is C 5 alkynyl. In some embodiments, R 1 is C 6 alkynyl.

[0275] In some embodiments, R 1 is C 1 -C 6 haloalkyl or C 1 -C 6 alkoxy.

[0276] In some embodiments, R 1 is C 1 -C 6 haloalkyl.

[0277] In some embodiments, R 1 is halomethyl. In some embodiments, R 1 is haloethyl. In some embodiments, R 1 is halopropyl. In some embodiments, R 1 is halobutyl. In some embodiments, R 1 is halopentyl. In some embodiments, R 1 is halohexyl.

[0278] In some embodiments, R 1 is C 1 -C 6 alkoxy.

[0279] In some embodiments, R 1 is methoxy. In some embodiments, R 1 is ethoxy. In some embodiments, R 1 is propoxy. In some embodiments, R 1 is butoxy. In some embodiments, R 1 is pentoxy. In some embodiments, R 1 is hexyloxy.

[0280] In some embodiments, R 1 is C 3 -C 12 cycloalkyl.

[0281] In some embodiments, R 1 is C 3 -C 6 cycloalkyl.

[0282] In some embodiments, R 1 is C 3It is cycloalkyl. In some embodiments, R 1 is C 4 cycloalkyl. In some embodiments, R 1 is C 5 cycloalkyl. In some embodiments, R 1 is C 6 cycloalkyl.

[0283] In some embodiments, R 1 is C 7 cycloalkyl. In some embodiments, R 1 is C 8 cycloalkyl. In some embodiments, R 1 is C 9 cycloalkyl. In some embodiments, R 1 is C 10 cycloalkyl. In some embodiments, R 1 is C 11 cycloalkyl. In some embodiments, R 1 is C 12 cycloalkyl.

[0284] In some embodiments, R 1 is Cl, Br, I, CF 3 , cyclopropyl, methyl, isopropyl, or cyclopentyl.

[0285] As generally defined herein, R 6 is H, halo, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy.

[0286] In some embodiments, R 6 is H.

[0287] In some embodiments, R 6 is halo, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy.

[0288] In some embodiments, R 6 is halo or -OH.

[0289] In some embodiments, R 6 is halo.

[0290] In some embodiments, R 6 is F, Cl, Br, or I. In some embodiments, R 6 is F, Cl, or Br.

[0291] In some embodiments, R 6 is F. In some embodiments, R 6 is Cl. In some embodiments, R 6 is Br. In some embodiments, R 6 is I.

[0292] In some embodiments, R 6 is -OH.

[0293] In some embodiments, R 6 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6It is an alkoxy group.

[0294] In some embodiments, R 6 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl.

[0295] In some embodiments, R 6 is C 1 -C 6 alkyl.

[0296] In some embodiments, R 6 is methyl. In some embodiments, R 6 is ethyl. In some embodiments, R 6 is propyl. In some embodiments, R 6 is butyl. In some embodiments, R 6 is pentyl. In some embodiments, R 6 is hexyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is isobutyl. In some embodiments, R 6 is isopentyl. In some embodiments, R 6 is isohexyl. In some embodiments, R 6 is sec-butyl. In some embodiments, R 6 is sec-pentyl. In some embodiments, R 6 is sec-hexyl. In some embodiments, R 6 is tert-butyl.

[0297] In some embodiments, R 6 is C 2 -C 6 alkenyl.

[0298] In some embodiments, R 6 is C 2 alkenyl. In some embodiments, R 6 is C 3 alkenyl. In some embodiments, R 6 is C 4 alkenyl. In some embodiments, R 6 is C 5 alkenyl. In some embodiments, R 6 is C 6 alkenyl.

[0299] In some embodiments, R 6 is C 2 -C 6 alkynyl.

[0300] In some embodiments, R 6 is C 2 alkynyl. In some embodiments, R 6 is C 3 alkynyl. In some embodiments, R 6 is C 4 alkynyl. In some embodiments, R 6 is C 5 alkynyl. In some embodiments, R 6 is C 6 alkynyl.

[0301] In some embodiments, R 6 is C 1 -C 6 haloalkyl or C 1 -C 6 alkoxy.

[0302] In some embodiments, R 6 is C 1 -C 6 haloalkyl.

[0303] In some embodiments, R 6 is halomethyl. In some embodiments, R6 is haloethyl. In some embodiments, R 6 is halopropyl. In some embodiments, R 6 is halobutyl. In some embodiments, R 6 is halopentyl. In some embodiments, R 6 is halohexyl.

[0304] In some embodiments, R 6 is C 1 -C 6 alkoxy.

[0305] In some embodiments, R 6 is methoxy. In some embodiments, R 6 is ethoxy. In some embodiments, R 6 is propoxy. In some embodiments, R 6 is butoxy. In some embodiments, R 6 is pentoxy. In some embodiments, R 6 is hexyloxy.

[0306] In some embodiments, R 6 is H, F, or -OH.

[0307] As generally defined herein, R 6’ is H, halo, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy.

[0308] In some embodiments, R 6’ is H.

[0309] In some embodiments, R 6’ is a halo, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy.

[0310] In some embodiments, R 6’ is a halo or -OH.

[0311] In some embodiments, R 6’ is a halo.

[0312] In some embodiments, R 6’ is F, Cl, Br, or I. In some embodiments, R 6’ is F, Cl, or Br.

[0313] In some embodiments, R 6’ is F. In some embodiments, R 6’ is Cl. In some embodiments, R 6’ is Br. In some embodiments, R 6’ is I.

[0314] In some embodiments, R 6’ is -OH.

[0315] In some embodiments, R 6’ is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy.

[0316] In some embodiments, R 6’ is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl.

[0317] In some embodiments, R 6’ is C 1 -C 6 alkyl.

[0318] In some embodiments, R 6’ is methyl. In some embodiments, R 6’ is ethyl. In some embodiments, R 6’ is propyl. In some embodiments, R 6’ is butyl. In some embodiments, R 6’ is pentyl. In some embodiments, R 6’ is hexyl. In some embodiments, R 6’ is isopropyl. In some embodiments, R 6’ is isobutyl. In some embodiments, R 6’ is isopentyl. In some embodiments, R 6’ is isohexyl. In some embodiments, R 6’ is sec-butyl. In some embodiments, R 6’ is sec-pentyl. In some embodiments, R 6’ is sec-hexyl. In some embodiments, R 6’ is tert-butyl.

[0319] In some embodiments, R 6’ is C 2 -C 6 alkenyl.

[0320] In some embodiments, R 6’ is C2 is alkenyl. In some embodiments, R 6’ is C 3 is alkenyl. In some embodiments, R 6’ is C 4 is alkenyl. In some embodiments, R 6’ is C 5 is alkenyl. In some embodiments, R 6’ is C 6 is alkenyl.

[0321] In some embodiments, R 6’ is C 2 -C 6 is alkynyl.

[0322] In some embodiments, R 6’ is C 2 is alkynyl. In some embodiments, R 6’ is C 3 is alkynyl. In some embodiments, R 6’ is C 4 is alkynyl. In some embodiments, R 6’ is C 5 is alkynyl. In some embodiments, R 6’ is C 6 is alkynyl.

[0323] In some embodiments, R 6’ is C 1 -C 6 is haloalkyl or C 1 -C 6 is alkoxy.

[0324] In some embodiments, R 6’ is C 1 -C 6 is haloalkyl.

[0325] In some embodiments, R 6’ is halomethyl. In some embodiments, R 6’ is haloethyl. In some embodiments, R6’ is halopropyl. In some embodiments, R 6’ is halobutyl. In some embodiments, R 6’ is halopentyl. In some embodiments, R 6’ is halohexyl.

[0326] In some embodiments, R 6’ is C 1 -C 6 alkoxy.

[0327] In some embodiments, R 6’ is methoxy. In some embodiments, R 6’ is ethoxy. In some embodiments, R 6’ is propoxy. In some embodiments, R 6’ is butoxy. In some embodiments, R 6’ is pentoxy. In some embodiments, R 6’ is hexyloxy.

[0328] In some embodiments, R 6’ is H, F, CF 3 , methoxy, or -OH.

[0329] As generally defined herein, R 6” is H, halo, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy.

[0330] In some embodiments, R 6” is H.

[0331] In some embodiments, R 6”is halo, -OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy.

[0332] In some embodiments, R 6” is halo or -OH.

[0333] In some embodiments, R 6” is halo.

[0334] In some embodiments, R 6” is F, Cl, Br, or I. In some embodiments, R 6” is F, Cl, or Br.

[0335] In some embodiments, R 6” is F. In some embodiments, R 6” is Cl. In some embodiments, R 6” is Br. In some embodiments, R 6” is I.

[0336] In some embodiments, R 6” is -OH.

[0337] In some embodiments, R 6” is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy.

[0338] In some embodiments, R 6” is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl.

[0339] In some embodiments, R 6” is C 1 -C 6 alkyl.

[0340] In some embodiments, R 6” is methyl. In some embodiments, R 6” is ethyl. In some embodiments, R 6” is propyl. In some embodiments, R 6” is butyl. In some embodiments, R 6” is pentyl. In some embodiments, R 6” is hexyl. In some embodiments, R 6” is isopropyl. In some embodiments, R 6” is isobutyl. In some embodiments, R 6” is isopentyl. In some embodiments, R 6” is isohexyl. In some embodiments, R 6” is sec-butyl. In some embodiments, R 6” is sec-pentyl. In some embodiments, R 6” is sec-hexyl. In some embodiments, R 6” is tert-butyl.

[0341] In some embodiments, R 6” is C 2 -C 6 alkenyl.

[0342] In some embodiments, R 6” is C 2is alkenyl. In some embodiments, R 6” is C 3 alkenyl. In some embodiments, R 6” is C 4 alkenyl. In some embodiments, R 6” is C 5 alkenyl. In some embodiments, R 6” is C 6 alkenyl.

[0343] In some embodiments, R 6” is C 2 -C 6 alkynyl.

[0344] In some embodiments, R 6” is C 2 alkynyl. In some embodiments, R 6” is C 3 alkynyl. In some embodiments, R 6” is C 4 alkynyl. In some embodiments, R 6” is C 5 alkynyl. In some embodiments, R 6” is C 6 alkynyl.

[0345] In some embodiments, R 6” is C 1 -C 6 haloalkyl or C 1 -C 6 alkoxy.

[0346] In some embodiments, R 6” is C 1 -C 6 haloalkyl.

[0347] In some embodiments, R 6” is halomethyl. In some embodiments, R 6” is haloethyl. In some embodiments, R 6”is halopropyl. In some embodiments, R 6” is halobutyl. In some embodiments, R 6” is halopentyl. In some embodiments, R 6” is halohexyl.

[0348] In some embodiments, R 6” is C 1 -C 6 alkoxy.

[0349] In some embodiments, R 6” is methoxy. In some embodiments, R 6” is ethoxy. In some embodiments, R 6” is propoxy. In some embodiments, R 6” is butoxy. In some embodiments, R 6” is pentoxy. In some embodiments, R 6” is hexyloxy.

[0350] In some embodiments, R 6” is H or F.

[0351] In some embodiments, R 1 is halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl, where R 6 is H, halo, or -OH, and R 6’ is H, halo, -OH, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 1 -C 3 alkoxy, and R 6” is H or halo.

[0352] In some embodiments, the 6,5-bicyclic core of formula (viii):

Chem.

Chem.

[0353] In some embodiments of formula (viii-a), the 6,5-bicyclic core is of the formula:

Chem.

[0354] In some embodiments of formula (viii-c), the 6,5-bicyclic core is of the formula: [Chemical formula] is as follows.

[0355] In some embodiments of formula (viii-d), the 6,5-bicyclic core has the formula: [Chemical formula] is as follows.

[0356] In some embodiments of formula (viii-e), the 6,5-bicyclic core has the formula: [Chemical formula] is as follows.

[0357] (d) Additional embodiments For the compounds of the present disclosure, the variables R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6’ , R 6” , R 7 , Z, L 1 , L 2 , n, and p may each independently be selected from the groups described herein, where applicable, and for any of the variables R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6’ , R 6” , R 7 , Z, L 1 , L 2 , n, and p, any group described herein, where applicable, for the remaining variables R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6’ , R 6” , R 7, Z, L 1 , L 2 It is understood that it may be combined with any group described herein for one or more of n, and p.

[0358] For example, -R 4- In some embodiments where Z is a group of formula (i), provided is a compound of formula (I-B):

Chemical formula

[0359] -R 4- In some embodiments where -R

Chemical formula

[0360] -R 4- In some embodiments where Z is a group of formula (iv), provided is a compound of formula (I-D):

Chemical formula

[0361] In some embodiments where the 6,5-bicyclic core of formula (viii) is of formula (viii-c), provided is a compound of formula (I-E):

Chemical formula

[0362] In some embodiments where the 6,5-bicyclic core of formula (viii) is of formula (viii-d), provided is a compound of formula (I-F):

Chemical formula

[0363] In some embodiments where the 6,5 - bicyclic core of formula (viii) is of formula (viii - e), provided is a compound of formula (I - G): [Chemical formula] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof. In some embodiments, R 1 is halo, C 1 - C 3 alkyl, C 1 - C 3 haloalkyl, or C 3 - C 5 cycloalkyl, R 6’ is halo, - OH, C 1 - C 3 alkyl, C 1 - C 3 haloalkyl, or C 1 - C 3 alkoxy, R 6” is halo. In some embodiments, R 1 is halo, C 1 - C 3 alkyl, C 1 - C 3 haloalkyl, or C 3 - C 5 cycloalkyl, R 6’ is halo, R 6” is halo. In some embodiments, R 1 is C 3 cycloalkyl, R 6’ is halo, R 6” is halo. In some embodiments, R 1 is C 3 cycloalkyl, R 6’ is fluoro, R 6” is fluoro. In some embodiments, each R2 and R 3 is H. In some embodiments, Z is -(L 2 ) n -carboxylic acid. In some embodiments, -R 4- the Z group is of formula (iv). In some embodiments, -R 4- the Z group is of formula (iv-a), (iv-b), (iv-c), or (iv-h). In some embodiments, -R 4- in the Z group of formula (iv-b) is of formula (iv-b-2). In some embodiments, -R 4- in the Z group of formula (iv-c) is of formula (iv-c-1). In some embodiments, -R 4- in the Z group of formula (iv-c) is of formula (iv-c-2). In some embodiments, -R 4- in the Z group of formula (iv-h) is of formula (iv-h-1). In some embodiments, -R 4- in the Z group of formula (iv-h) is of formula (iv-h-2). In some embodiments, -R 4- in the Z group of formula (iv-h) is of formula (iv-h-3). In some embodiments, -R 4- in the Z group of formula (iv-h) is of formula (iv-h-4). In some embodiments, each R 5 is independently the same or different and is selected from fluoro or C 1 - 3 alkyl. In some embodiments, both Rs 5 cyclize with the atom to which they are attached to form C 3 cycloalkyl.

[0364] In some embodiments, the compound is selected from the compounds of Table 1 or 2, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof. Compounds containing a tetrazolyl (Z) group may contain a mixture of tetrazolyl tautomers. In some embodiments, the compound is a compound described in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a neutral (free base) compound of Table 1 or 2. In some embodiments, the compound is a pharmaceutically acceptable salt of a compound described in Table 1 or Table 2. Tables 1 and 2 provide the positions of the compounds provided in Examples (Ex) by example number or in Table A (TA) of the examples. An asterisk (*) next to the compound number (#) means that any stereochemistry has been assigned.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

[0365] In some embodiments, the compound is Compound 58 (e.g., Compound 58A*), Compound 59A, Compound 60A*, Compound 61A, Compound 61B, Compound 62A, Compound 63A, Compound 64A, Compound 66, Compound 67C*, or Compound 67D*, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof.

[0366] In some embodiments, the compound is compound 58 (e.g., compound 58A*), compound 59A, compound 60A*, compound 61A, compound 61B, compound 62A, compound 63A, compound 64A, compound 66, compound 67C*, or compound 67D*, or a pharmaceutically acceptable salt thereof.

[0367] In some embodiments, the compound is the free base of compound 58 (e.g., compound 58A*), compound 59A, compound 60A*, compound 61A, compound 61B, compound 62A, compound 63A, compound 64A, compound 66, compound 67C*, or compound 67D*.

[0368] In some embodiments, the compound is a compound of formula (I), or an isotopically derivative of any of the compounds provided in Table 1 or 2. In some embodiments, the isotopically derivative is 2 H, 13 C, 14 C, 15 N, 18 O, 29 Si, 31 P, and 34 S, enriched or labeled with respect to one or more atoms selected from. In some embodiments, the isotopically derivative is a compound labeled with deuterium (i.e., enriched with 2 H with respect to one or more of its atoms). In some embodiments, the compound is 18 a compound labeled with F. In some embodiments, the compound is 123 a compound labeled with 124 I, 125 a compound labeled with 129 I, 131 a compound labeled with 135 I, 33 a compound labeled with 34 S, 35 a compound labeled with 36 S, or any combination thereof. In some embodiments, the compound is 33 a compound labeled with 34 S, 35 a compound labeled with 36 S, 35 a compound labeled with 36 S, 36 a compound labeled with 36 S, or any combination thereof. In some embodiments, the compound is 33 a compound labeled with 34 S, 35 a compound labeled with 36 S, 35 a compound labeled with 36 S, 36 a compound labeled with 36 S, or any combination thereof. In some embodiments, the compound is 33 a compound labeled with 34 S, 35 a compound labeled with 36 S, 35 a compound labeled with 36 S, 36 a compound labeled with 36 S, or any combination thereof. In some embodiments, the compound is 33 a compound labeled with 34 S, 35 a compound labeled with 36 S, 35 a compound labeled with 36 S, 36 a compound labeled with 36 S, or any combination thereof. In some embodiments, the compound is 33 a compound labeled with 34 S, 35 a compound labeled with 36 S, 35 a compound labeled with 36 S, 36 a compound labeled with 36 S, or any combination thereof. In some embodiments, the compound is 33 a compound labeled with 34 S, 35 a compound labeled with 36 S, 35 a compound labeled with 36 S, 36 a compound labeled with 36 S, or any combination thereof. In some embodiments, the compound is 33 a compound labeled with 34 S, 35 a compound labeled with 36 S, 35 a compound labeled with 36 S, 36 a compound labeled with 36 S, or any combination thereof. In some embodiments, the compound is 33 a compound labeled with 34 S, 35 a compound labeled with 36 S, 35 a compound labeled with 36 S, 36 a compound labeled with 36 S, or any combination thereof. In some embodiments, the compound is 33 a compound labeled with 34 S, 35 a compound labeled with 36 S, 35 a compound labeled with 36 S, 36 a compound labeled with 36 S, or any combination thereof. In some embodiments, the compound is 33 a compound labeled with 34 S, 35 a compound labeled with 36 S, 35 a compound labeled with 36 S, 36 a compound labeled with 36 S, or any combination thereof. In some embodiments, the compound is 33 a compound labeled with 34 S, 35 a compound labeled with 36 S, 35 a compound labeled with 36 S, 36 a compound labeled with <Compounds labeled with S, or any combination thereof.

[0369] 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and / or 36 It is understood that the compounds labeled with S can be prepared using any of the techniques recognized in various technical fields. For example, deuterium-labeled compounds are generally prepared by replacing non-isotope-labeled reagents with 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and / or 36 reagents labeled with S. The aforementioned 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and 36 compounds containing one or more of the S atoms are within the scope of the present disclosure. Further, isotopes (e.g., 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and / or 36Replacement by (S) can result in certain therapeutic advantages due to greater metabolic stability, e.g., increased half-life in vivo or reduced required dose.

[0370] In some embodiments, the isotope derivative is a deuterium-labeled compound of any one of the compounds of the formulae disclosed herein.

[0371] It is understood that the isotope derivatives can be prepared using any of the techniques recognized in the various art fields. For example, the isotope derivatives can generally be prepared by replacing non-isotope-labeled reagents with isotope-labeled reagents by carrying out the procedures disclosed in the schemes and / or examples described herein.

[0372] (2) Method of preparation It should be understood that the compounds of the present disclosure can be prepared in various ways using standard synthetic methods and procedures known to those skilled in the art or apparent to those skilled in the art in light of the teachings herein, using commercially available starting materials, compounds known in the literature, or readily preparable intermediates. Standard synthetic methods and procedures for the preparation of organic molecules and for the conversion and manipulation of functional groups can be obtained from the relevant scientific literature or standard texts in the field. Without being limited to any one or several sources, classical texts such as Smith, M.B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001, Greene, T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989), L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994), and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) (incorporated herein by reference) are useful and recognized reference texts for organic synthesis known to those skilled in the art.

[0373] One skilled in the art will note that the order of certain steps, such as the introduction and removal of protecting groups, can be changed between the reaction sequences and synthetic schemes described herein. One skilled in the art will recognize that a particular group may require protection from reaction conditions via the use of a protecting group. Protecting groups can also be used to distinguish similar functional groups in a molecule. A list of protecting groups and methods for their introduction and removal can be found in Greene, T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999. By way of example, a carboxylic acid protecting group (PG) can include a C 1-6 alkyl, C 6 aryl, or aryl C 1-6 alkyl group, where the alkyl and aryl are optionally substituted with halo, alkyl, or alkoxy groups. In some embodiments, the carboxylic acid protecting group (PG) is methyl (-CH 3 , Me), ethyl (-CH 2 CH 3 , Et), or t-butyl (-C(CH 3 ) 3 , tBu).

[0374] In the synthetic schemes described herein, a compound may be shown in one particular configuration for the sake of simplicity. Such a particular configuration should not be construed as limiting the present disclosure to one or another isomer, tautomer, positional isomer, or stereoisomer, nor is it exclusive of mixtures of isomers, tautomers, positional isomers, or stereoisomers, but it should be understood that a given isomer, tautomer, positional isomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, positional isomer, or stereoisomer.

[0375] Preferred general methods for preparing the compounds of formula (I) and the intermediates useful in the synthesis of such compounds are provided in the following general schemes 1-12. The examples also describe non-limiting procedures for the preparation of such compounds.

[0376] General Scheme 1 [Chem.] [Chem.] Z is -(L 2 ) n The compound of formula (I) wherein Z is -(L)-tetrazole can be prepared as shown in General Scheme 1 by amide coupling of a substituted indolinone (acetic acid) (i), or a salt thereof, with an aminotetrazole (ii), or a salt thereof, to obtain a target tetrazole analog (iii) or (iii-a), or a salt thereof, wherein the indolinone (acetic acid) (i) and the aminotetrazole (ii) are either commercially available or known from the chemical literature unless otherwise indicated, and the dashed line corresponds to an optional spiro-fused cycloalkyl.

[0377] General Scheme 2 [Chem.] [Chem.] Z is -(L 2 ) n The compound of formula (I) wherein Z is -(L)-carboxylic acid is prepared by amide coupling of a substituted indolinone (acetic acid) (i), or a salt thereof, with an amino ester (iv), or a salt thereof, wherein PG is a protecting group such as C 1-6 alkyl, C 6 aryl, or aryl-C 1-6 alkyl group, and alkyl and aryl are each optionally substituted with one or more halo, C 1-6 alkyl, or C 1-6Optionally substituted with an alkoxy group), followed by hydrolysis to obtain the target carboxylic acid analog (v), or (v-a), or a salt thereof, and can be prepared by the two-step process shown in General Scheme 2, where indolinone (acetic acid) (i) and amino ester (iv) are either commercially available or known in the chemical literature unless otherwise indicated, and the dashed line corresponds to an optional spiro-fused cycloalkyl.

[0378] In some embodiments, the compounds of the present disclosure are

Chemical formula

[0379] In some embodiments, PG is C 1-6 alkyl, C 6 aryl, or aryl-C 1-6 alkyl, where the alkyl and aryl are optionally substituted with one or more halos, C 1-6 alkyl, or C 1-6 alkoxy.

[0380] In some embodiments, PG is C 1-6 alkyl, C 6 aryl, or aryl-C 1-6 alkyl.

[0381] In some embodiments, PG is C 1-6 alkyl optionally substituted with one or more halos, C 1-6 alkoxy, or C 1-6 alkyl.

[0382] In some embodiments, PG is C 1-6 alkyl.

[0383] In some embodiments, PG is C 1-6 alkyl optionally substituted with one or more halos, C 1-6 alkoxy, or C 6It is aryl.

[0384] In some embodiments, PG is C 6 It is aryl.

[0385] In some embodiments, PG is aryl-C 1-6 It is alkyl, and the alkyl and aryl are optionally substituted with one or more halos, C 1-6 alkyl, or C 1-6 alkoxy.

[0386] In some embodiments, PG is aryl-C 1-6 It is alkyl.

[0387] Exemplary compounds of formula (v-o) include any of the compounds provided in Table 3, or salts thereof, or pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, stereoisomers, tautomers, isotope derivatives, or polymorphs thereof. In some embodiments, the compound of formula (v-o) is a prodrug.

Table 3-1

Table 3-2

Table 3-3

Table 3-4

Table 3-5

Table 3-6

Table 3-7

Table 3-8

[0388] General Scheme 3 [Chem.] [Chem.] The compound of formula (I) can be prepared as shown in General Scheme 3 by alkylation of indolinone (vi), or a salt thereof, followed by hydrolysis to obtain indolinone (acetic acid) (i), or a salt thereof. Subsequently, by amide coupling (and subsequent hydrolysis if the target is a carboxylic acid and not a tetrazole), the target carboxylic acid analog (v), or (v-a), or a salt thereof, or the target tetrazole analog (iii-a), or a salt thereof is obtained, and the starting materials indolinone (vi), amino ester (iv), and aminotetrazole (ii) are either commercially available or known from the chemical literature unless otherwise indicated, and the dashed line corresponds to any spiro-fused cycloalkyl.

[0389] General Scheme 4 [Chem.] [Chem.] The compound of formula (I) is prepared by transhalogenating bromoindolinone (vii), or a salt thereof (wherein PG is a protecting group such as C 1-6 alkyl, C 6 aryl, or aryl-C 1-6 alkyl group, and alkyl and aryl are optionally substituted with one or more halo, C 1-6 alkyl, or C 1-6 alkoxy groups) to form iodoindolinone (viii), or a salt thereof, and then copper coupling to -CF 3Obtain analog (ix) or its salt, then perform ester hydrolysis to obtain carboxylic acid intermediate (x) or its salt, and subsequently carry out amide coupling with (iv) or (ii), or its salt (in the case where the target is a carboxylic acid and not a tetrazole, followed by hydrolysis), to obtain carboxylic acid target analog (xi) or (v-b), or its salt, or tetrazole target analog (iii-b), or its salt, as can be prepared as shown in general scheme 4. The starting materials indolinone (vii), amino ester (iv), and aminotetrazole (ii) are either commercially available, known in the chemical literature, or can be prepared through the previous schemes in this specification, unless otherwise indicated. The dashed line corresponds to any spiro-fused cycloalkyl.

[0390] General Scheme 5

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0391] General Scheme 6

Chemical formula

Chemical formula

[0392] General Scheme 7

Chemical formula

Chemical formula

[0393] General Scheme 8

Chemical Structure

Chemical Structure

[0394] General Scheme 9 [Chemical Formula] [Chemical Formula] R 1 is -Br, and R 6 ' is C 1 -C 6 A compound of formula (I) that is alkoxy (e.g., -OR 6a (wherein R 6a is C 1 -C 6)) which is alkyl can be prepared by the process shown in General Scheme 9 through alkylation of hydroxyindolinone carboxylic acid (xxiv) or its salt, followed by ester hydrolysis to obtain carboxylic acid intermediate (xxxiii) or its salt. Subsequently, by amide coupling (and hydrolysis thereafter when the target is a carboxylic acid and not a tetrazole), carboxylic acid target analog (xxxiv) or (v-g), or its salt, and tetrazole target analog (iii-g), or its salt are obtained. Indolinone (xxiv), amino ester (iv), and aminotetrazole (ii) are either commercially available, known in the chemical literature, or prepared through the previous schemes herein, unless otherwise indicated. The dashed line corresponds to any spiro-fused cycloalkyl.

[0395] General Scheme 10 [Chemical Formula] [Chemical Formula] R 1 is -I or -Br, and for a compound of formula (I) where R 6 ’ is -OH, (xxiv) or its salt is subjected to amide coupling (wherein PG is a protecting group such as C 1-6 alkyl, C 6 aryl, or aryl-C 1-6 alkyl group, and alkyl and aryl may have one or more halo, C 1-6 alkyl, or C 1-6(Optionally substituted with an alkoxy group) to obtain an ester intermediate (xxxv), or a salt thereof, followed by copper-mediated transhalogenation (and subsequent hydrolysis if the target is a carboxylic acid and not a tetrazole) to obtain a carboxylic acid target analog (xxxvii), or (v-h), or a salt thereof, and a tetrazole target analog (iii-h-a) and (iii-h-b), or a salt thereof, can be prepared by the process shown in General Scheme 10, and indolinone (xxiv), amino ester (iv), and amino tetrazole (ii) are commercially available, known in the chemical literature, or can be prepared through the previous schemes herein, unless otherwise indicated, and the dashed line corresponds to any spiro-fused cycloalkyl.

[0396] General Scheme 11

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

[0397] General Scheme 12

Chemical Structure

Chemical Structure

[0398] (3) Biological assay Once produced, the compounds designed, selected, and / or optimized by the above methods can be characterized using various assays known to those skilled in the art to determine whether the compound has biological activity. For example, the molecule can be characterized by conventional assays including, but not limited to, the assays described below, to determine whether it has predicted activity, binding activity, and / or binding specificity. The effectiveness of the compounds of the present disclosure can be determined by industry-acceptable assays / disease models according to standard practices that elucidate the same as those described in the art and found in current general knowledge.

[0399] Furthermore, high-throughput screening can be used to accelerate analysis using such assays. As a result, it may be possible to rapidly screen the molecules described herein for activity using techniques known in the art. For example, Devlin (1998) High Throughput Screening, Marcel Dekker and U.S. Patent No. 5,763,263 describe general methodologies for performing high-throughput screening. High-throughput assays can use one or more different assay technologies, including but not limited to those described below.

[0400] A variety of in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, binding assays, cell assays (cell lines, primary cells, and whole blood), in vitro cell viability assays, and assays for determining the potency, unbound clearance, solubility, and permeability of NLRP3.

[0401] In some embodiments, the compounds of the present disclosure can be tested for their human-NLRP3 inhibitory activity using known procedures such as those reported in Coll et al. Nat Med. (2015) 21(3):248-255. See also the Examples, Section on Biological Assay Methods.

[0402] In some embodiments, the compounds of the present disclosure can be tested for unbound clearance (Clu) according to known procedures such as those described in Miller et al., J. Med. Chem. (2020) 63:12156-12170. For example, unbound clearance (Clu) can be calculated by dividing the total clearance (CL in mL / min / kg units) measured in blood or plasma by the unbound fraction (fu) in plasma.

[0403] In some embodiments, the solubility of the compounds of the present disclosure can be determined according to known procedures such as those described in Alsenz and Kansy, Advanced Drug Delivery Reviews (2007) 59:546-567 and Wang et al. J Mass Spectrom. (2000) 35:71-76. For example, the dynamic solubility in a physiologically relevant medium can be measured using serial dilution and a 2-hour incubation period, followed by filtration, and can be reported in mM units by LC-MS / MS. The thermodynamic solubility in a physiologically relevant medium can be measured by LC-MS / MS after a 24-hour incubation, followed by filtration, and can be reported in mg / mL units.

[0404] (4) Pharmaceutical composition In some embodiments, the present disclosure provides a pharmaceutical composition comprising, as an active ingredient, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, and one or more of pharmaceutically acceptable diluents, carriers, or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) selected from Table 1 or 2, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, and one or more of pharmaceutically acceptable diluents, carriers, or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) selected from Table 1, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, and one or more of pharmaceutically acceptable diluents, carriers, or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) selected from Table 2, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, and one or more of pharmaceutically acceptable diluents, carriers, or excipients.

[0405] The pharmaceutical composition can be administered orally, nasally, transdermally, by the pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenterally. In one embodiment, the pharmaceutical composition is administered orally.

[0406] Compounds of formula (I) can all be formulated for oral use, for example, as tablets, pills, hard or soft capsules (each of which may contain sustained release or timed release formulations), lozenges, suspensions (e.g., aqueous or oily suspensions), emulsions, powders (e.g., dispersible powders), granules, syrups, elixirs, and tinctures, using forms well known to those skilled in the pharmaceutical art; for topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions); for administration by inhalation (e.g., as finely divided powders or liquid aerosols); for administration by insufflation (e.g., as finely divided powders); or for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous (bolus or infusion), subcutaneous, intramuscular, intraperitoneal, or intramuscular injection, or as suppositories for rectal administration); or for transdermal (e.g., patch) administration.

[0407] Routes of administration include oral (e.g., by ingestion); buccal; sublingual; transdermal (e.g., by patch, plaster, etc.); transmucosal (e.g., by patch, plaster, etc.); intranasal (e.g., by nasal spray); intraocular (e.g., by eye drops); pulmonary (e.g., via aerosol, e.g., via mouth or nose, e.g., by inhalation or insufflation therapy); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intramedullary, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, and intrasternal; including, but not limited to, by implantation of a depot or reservoir subcutaneously or intramuscularly.

[0408] The formulation can be in the form of an aqueous solution containing an aqueous vehicle. The aqueous vehicle component can include water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include solubilizers, chelating agents, preservatives, tonicity agents, viscosity / suspending agents, buffers, and pH adjusters, and mixtures thereof.

[0409] Any suitable solubilizing agent can be used. Examples of solubilizing agents include those selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof, such as cyclodextrins.

[0410] Any suitable chelating agent can be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0411] Any suitable preservative can be used. Examples of preservatives include those selected from the group consisting of benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof, such as quaternary ammonium salts.

[0412] The aqueous vehicle may also contain a tonicity agent for adjusting the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, triethylene glycol, etc.), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0413] The aqueous vehicle may contain a viscosity / suspending agent. Suitable viscosity / suspending agents include cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400, etc.), carboxymethylcellulose, hydroxypropylmethylcellulose, and crosslinked acrylic acid polymers (carbomers) crosslinked with polyalkenyl ether or divinyl glycol (Carbopol - for example, Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0414] To adjust the formulation to an acceptable pH (typically in the pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH modifier. The pH modifier is typically a mineral acid or metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH modifiers are added to adjust the formulation to the target acceptable pH range. Thus, it may not be necessary to use both an acid and a base, and depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0415] The aqueous vehicle may also contain a buffer to stabilize the pH. When used, the buffer solution is selected from the group consisting of phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffer (such as boric acid or its salts containing disodium tetraborate), citrate buffer (such as citric acid or its salts containing sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0416] The formulation may further contain a wetting agent. Suitable classes of wetting agents include polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0417] Oral compositions generally contain an inert diluent or a pharmaceutically acceptable carrier for food use. They can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouse wash, in which the compound in the fluid carrier is applied orally, gargled, expectorated, or swallowed. Pharmaceutically compatible binders and / or adjuvant substances can be included as part of the composition. Tablets, pills, capsules, troches, etc. can contain any of the following ingredients or compounds of similar nature: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, primogel, or corn starch; lubricants such as magnesium stearate or steroite; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavor.

[0418] Compositions intended for oral use can further contain, for example, one or more colorants, sweeteners, flavors, and / or preservatives.

[0419] The compound of formula (I), or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, or a pharmaceutical composition containing them, can be administered alone as monotherapy or in addition to one or more other substances and / or treatments. Such combination therapies can be achieved by simultaneous, sequential, or separate administration of the individual components of the therapy.

[0420] For example, the therapeutic efficacy can be enhanced by the administration of an adjuvant (i.e., by itself, the adjuvant may have only minimal therapeutic utility, but in combination with another therapeutic agent, enhances the overall therapeutic utility to the individual). Alternatively, by way of example only, the benefit experienced by the subject can be increased by administering a compound of formula (I) together with another therapeutic agent (including a treatment regimen) that also has a therapeutic benefit.

[0421] In examples where a compound of formula (I) is administered in combination with another therapeutic agent, the compound need not be administered via the same route as the other therapeutic agent and can be administered by a different route due to different physical and chemical characteristics. For example, a compound of formula (I) can be administered orally to produce and maintain its good blood levels, while the other therapeutic agent can be administered intravenously.

[0422] The particular choice of the other therapeutic agent depends on the diagnosis of the attending physician, and the determination of the condition of the individual, and the appropriate treatment protocol. According to this aspect of the present disclosure, a combination is provided that includes a compound of formula (I) and another therapeutic agent for use in the treatment of a disease or disorder.

[0423] According to a further aspect of the present disclosure, a pharmaceutical composition is provided that includes a compound of formula (I), or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, in combination with another therapeutic agent and a pharmaceutical excipient.

[0424] (5) Methods of Use and Treatment The compound of formula (I) has been found to be useful as an inhibitor of NLRP3 activity.

[0425] In some embodiments, the compound of formula (I) modulates NLRP3. In some embodiments, the modulation is inhibition.

[0426] In some embodiments, provided is a method of doing so in a subject in need of treating a disease or disorder, the method comprising administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, or a pharmaceutical composition comprising the same. In some embodiments, the disease or disorder is associated with abnormal NLRP3 activity, and the method comprises inhibiting the abnormal NLRP3 activity such that the subject is treated.

[0427] In some embodiments, provided is a method of doing so in a subject in need of treating a disease or disorder, the method comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, or a pharmaceutical composition comprising the same.

[0428] In some embodiments, provided is a method of doing so in a subject in need of therapeutically treating a disease or disorder disclosed herein, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, or a pharmaceutical composition comprising the same.

[0429] In some embodiments, provided is a method of doing so in a subject in need of treating a disease or disorder disclosed herein, the method comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, or a pharmaceutical composition comprising the same.

[0430] In some embodiments, provided is a method of doing so in a subject in need of prophylactic treatment of a disease or disorder disclosed herein, the method comprising administering to the subject a prophylactically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, or a pharmaceutical composition comprising the same.

[0431] In some embodiments, provided is a method of doing so in a subject in need of prophylactic treatment of a disease or disorder disclosed herein, the method comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof, or a pharmaceutical composition comprising the same.

[0432] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the modulation of NLRP3.

[0433] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder disclosed herein.

[0434] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting NLRP3.

[0435] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0436] In some embodiments, the disease or disorder is a disease or disorder in which NLRP3 activity is involved.

[0437] In some embodiments, the disease or disorder is a disease or disorder of the central nervous system (CNS), a disease or disorder of the peripheral nervous system (PNS), a primary neurological disease of muscle, an inflammatory disorder, an autoimmune disorder, cancer, an infectious disease, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, a graft-versus-host disease, pain (including disorders related to pain management such as allodynia), or an NLRP3-related disease in a subject determined to have a germline or somatic non-silent mutation in NLRP3.

[0438] In some embodiments, the disease or disorder is a disease or disorder of the central nervous system and / or peripheral nervous system (PNS) such as dementia, Alzheimer's disease ("AD"), epilepsy, traumatic brain injury ("TBI"), multiple sclerosis ("MS"), developmental disorders, acute disseminated encephalomyelitis, transverse myelitis, Parkinson's disease ("PD"), amyotrophic lateral sclerosis ("ALS"), Huntington's disease ("HD"), or spinal cord injury.

[0439] In some embodiments, the disease or disorder is a primary neurological disease of muscle such as dystrophy or spinal muscular atrophy.

[0440] In some embodiments, the disease or disorder is an inflammatory disorder such as gout or inflammatory anemia.

[0441] In some embodiments, the disease or disorder is an autoimmune disease such as ulcerative colitis.

[0442] In some embodiments, the disease or disorder is cancer such as skin cancer or colon cancer.

[0443] In some embodiments, the disease or disorder is an infectious disease such as a neurological infectious disease.

[0444] In some embodiments, the disease or disorder is a metabolic disease such as diabetes, for example, type 2 diabetes.

[0445] In some embodiments, the disease or disorder is a cardiovascular disease such as stroke.

[0446] In some embodiments, the disease or disorder is a respiratory disease such as asthma (e.g., steroid-resistant asthma, severe steroid-resistant asthma) or chronic obstructive pulmonary disease ("COPD").

[0447] In some embodiments, the disease or disorder is a kidney disease such as acute kidney disease, chronic kidney disease, or rare kidney disease.

[0448] In some embodiments, the disease or disorder is a liver disease such as non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0449] In some embodiments, the disease or disorder is an eye disease such as optic neuritis or macular degeneration.

[0450] In some embodiments, the disease or disorder is a skin disease such as psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0451] In some embodiments, the disease or disorder is a lymphatic disease.

[0452] In some embodiments, the disease or disorder is a rheumatic disease such as osteoarthritis, dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0453] In some embodiments, the disease or disorder is a psychological disease such as a neuropsychiatric condition including depression, major depressive disorder, or treatment-resistant depression.

[0454] In some embodiments, the disease or disorder is graft-versus-host disease.

[0455] In some embodiments, the disease or disorder is pain (including disorders related to pain management) such as pain management dependence, osteoarthritis pain, or allodynia.

[0456] In some embodiments, the NLRP3-related disease in a subject determined to have a germline or somatic non-silent mutation in NLRP3 is a cryopyrin-associated autoinflammatory syndrome. In some embodiments, the cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal-onset multisystem inflammatory disease (NOMID).

[0457] In some embodiments, the disease or disorder is dementia, Alzheimer's disease ("AD"), epilepsy, traumatic brain injury ("TBI"), multiple sclerosis ("MS"), developmental disorder, acute disseminated encephalomyelitis, transverse myelitis, Parkinson's disease ("PD"), amyotrophic lateral sclerosis ("ALS"), spinal muscular atrophy, Huntington's disease ("HD"), spinal cord injury, dystrophy, neurological infection, pain management dependence disorder, neuropsychiatric condition (e.g., depression, major depressive disorder, treatment-resistant depression), neonatal-onset multisystem inflammatory disease ("NOMID"), asthma, osteoarthritis, ulcerative colitis, gout, inflammatory anemia, Still's disease, chronic obstructive pulmonary disease ("COPD"), osteoarthritis pain, or hidradenitis suppurativa.

[0458] In another aspect, provided is a method of inhibiting NLRP3 activity in a cell (e.g., in vitro or in vivo), the method comprising contacting the cell with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, tautomer, isotope derivative, prodrug, or polymorph thereof.

[0459] (6) Additional embodiments Embodiments 1-36 are further contemplated herein.

[0460] Embodiment 1: A compound of formula (I):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Examples

[0461] The following examples are described so that the present disclosure can be more fully understood. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the present disclosure in any way.

[0462] Analysis method The nuclear magnetic resonance (NMR) spectrum was recorded at 400 megahertz (MHz) and 300.3 K as described, unless otherwise specified, and the chemical shift (δ) was reported in parts per million (ppm). The spectra were recorded with 8, 16, or 32 scans using a Bruker Avance 400 instrument. Exemplary NMR solvents include deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD), and deuterated chloroform (CDCl 3 ). Other abbreviations: s = singlet; d = doublet; t = triplet; m = multiplet; br = broad.

[0463] Liquid chromatography - mass spectrometry (LCMS) and spectra were recorded using a Shimadzu LCMS - 2020. The injection volume was 0.7 - 8.0 μl and the flow rate was typically 0.8 or 1.2 ml / min. The detection methods were diode array (DAD) or evaporative light scattering (ELSD), and positive ion electrospray ionization (ESI). The MS range was 100 - 1000 Da. The solvent was a gradient of water (H 2 O) and / or acetonitrile (MeCN), and may contain modifiers such as formic acid (FA), trifluoroacetic acid (TFA), or ammonium carbonate (NH 4 HCO 3 ) (typically 0.01 - 0.04%). ESI or ES = electrospray ionization; m / z = mass / charge; RT = retention time (min).

[0464] Gas chromatography-mass spectrometry (GCMS) chromatograms and spectra were recorded using an Agilent GCMS8890-5977 and detector channel FID. GC parameters: DB-5MS, 12m×0.20mm×0.33um; column oven temperature: 50.0; injection volume: 0.5 μL; column flow: 1.2 ml / min; injection temperature: 300 °C; injection mode: split; split ratio: 20:1; detector temperature: 300 °C; initial temperature: 50 °C for 1 minute, then 40 °C / min to 300 °C for 1.75 minutes. Makeup gas: He; makeup flow: 25.0 mL / min; H2 flow: 30.0 mL / min; air flow: 400.0 mL / min; final temperature: 300 °C. MS detector acquisition mode: start time: 2.00 minutes; end time: 9.00 minutes; acquisition mode: scan; interface type: EI threshold: 150; scan speed: 1562; start m / z: 50.00; end m / z: 550.00; MS source: 230.00 °C; MS Quad: 150.00 °C; solvent cut time: 2.00 minutes.

[0465] Purification / separation method. The purification and / or separation chromatography methods used for the purification and / or isolation of exemplary compounds by a synthetic method are described. rf = retention coefficient; RT = retention time (minutes); preparative HPLC = preparative high performance liquid chromatography; preparative SFC = preparative supercritical fluid chromatography; TLC = thin layer chromatography.

[0466] Synthetic method Example 1: N-(3-(1H-tetrazol-5-yl)propyl)-2-(5-bromo-3,3-dimethyl-2-oxoindolin-1-yl)acetamide (tautomer 1) and N-(3-(2H-tetrazol-5-yl)propyl)-2-(5-bromo-3,3-dimethyl-2-oxoindolin-1-yl)acetamide (tautomer 2) (Compound 1)

Chemical formula

[0467] Example 2: 4-(2-(5-bromo-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoic acid (Compound 2) and methyl 4-(2-(5-bromo-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoate (Compound 2-OMe)

Chemical formula

[0468] Example 3: 4-(2-(5'-Bromo-2'-oxospiro[cyclopentane-1,3'-indoline]-1'-yl)acetamido)butanoic acid (Compound 5) and Methyl 4-(2-(5'-bromo-2'-oxospiro[cyclopentane-1,3'-indoline]-1'-yl)acetamido)butanoate (Compound 5-OMe)

Chemical Structure

[0469] Procedure 2: A solution of 2-(5'-bromo-2'-oxo-spiro[cyclopentane-1,3'-indoline]-1'-yl)acetic acid (1 equiv, 90 mg, 0.278 mmol) and methyl 4-aminobutanoate hydrochloride (1.1 equiv, 47 mg, 0.305 mmol) in 0.8 mL of N,N-dimethylformamide (DMF) was treated with N,N-diisopropylethylamine (DIPEA) (3 equiv, 0.15 mL, 0.833 mmol) and [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (1.1 equiv, 116 mg, 0.305 mmol) and stirred at room temperature for 20 min. Methyl 4-(2-(5'-bromo-2'-oxospiro[cyclopentane-1,3'-indoline]-1'-yl)acetamido)butanoate (Compound 5-OMe) was formed in situ. The mixture was then treated with a solution of 2N NaOH (5 equiv, 0.56 mL, 1.4 mmol) and stirred for an additional 2 h. The mixture was quenched upon addition of 6N HCl (0.23 mL). The residue was purified using reverse-phase chromatography eluting with 0-100% MeCN / H 2 O to afford 4-(2-(5'-bromo-2'-oxospiro[cyclopentane-1,3'-indoline]-1'-yl)acetamido)butanoic acid (Compound 5). LCMS (ES, m / z): RT = 2.20 min, m / z = 411.36 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.09 (s, 1H), 8.20 (t, J = 5.6 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.27 (s, 2H), 3.17 (s, 1H), 3.08 (q, J = 6.6 Hz, 2H), 2.23 (t, J = 7.4 Hz, 2H), 2.07 - 1.90 (m, 5H), 1.87 - 1.77 (m, 2H), 1.63 (p, J = 7.2 Hz, 2H).

[0470] Example 4: 4-(2-(3,3-Dimethyl-2-oxo-5-(trifluoromethyl)indolin-1-yl)acetamido)-4-methylpentanoic acid (Compound 8) and Methyl 4-(2-(3,3-dimethyl-2-oxo-5-(trifluoromethyl)indolin-1-yl)acetamido)-4-methylpentanoate (Compound 8-OMe) [Chemical formula] Step 1: In a 20 mL vial, methyl 2-(5-bromo-3,3-dimethyl-2-oxoindol-1-yl)acetate (280 mg, 0.897 mmol, 1 equivalent), copper(I) iodide (342 mg, 1.79 mmol, 2 equivalents), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (153 mg, 1.08 mmol, 1.2 equivalents), sodium iodide (161 mg, 1.08 mmol, 1.2 equivalents), and dioxane (5 mL) were added at 100 °C. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 12 hours. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with methanol (MeOH) (3 × 5 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to obtain methyl 2-(5-iodo-3,3-dimethyl-2-oxoindol-1-yl)acetate (240 mg, 75% yield) as a red oil. LCMS: (ES, m / z): RT = 1.15 min, m / z = 360.2 [M+H] + .

[0471] Step 2: To a 20 mL vial were added methyl 2-(5-iodo-3,3-dimethyl-2-oxoindol-1-yl)acetate (230 mg, 0.640 mmol, 1 equiv), copper (407 mg, 6.40 mmol, 10 equiv), diphenyl(trifluoromethyl)sulfonium (490 mg, 1.92 mmol, 3 equiv), and N,N-dimethylformamide (DMF) (3 mL) at 80 °C. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with methanol (MeOH) (2 × 4 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to afford methyl 2-[3,3-dimethyl-2-oxo-5-(trifluoromethyl)indol-1-yl]acetate (150 mg, 78% yield) as a red oil. LCMS: (ES, m / z): RT = 1.15 min, m / z = 302.1 [M+H] + .

[0472] Step 3: To an 8 mL vial were added methyl 2-[3,3-dimethyl-2-oxo-5-(trifluoromethyl)indol-1-yl]acetate (130 mg, 0.432 mmol, 1 equiv), lithium hydroxide (31.0 mg, 1.30 mmol, 3 equiv), methanol (MeOH) (2 mL), and water (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The mixture was acidified to pH 3 with HCl (2 aqueous solution). The aqueous layer was extracted with ethyl acetate (EtOAc) (3 × 10 mL). The resulting mixture was concentrated under reduced pressure. This afforded [3,3-dimethyl-2-oxo-5-(trifluoromethyl)indol-1-yl]acetic acid (100 mg, 81% yield) as a white solid. LCMS: (ES, m / z): RT = 0.68 min, m / z = 288.1 [M+H] + .

[0473] Procedure 4: To an 8 mL vial were added [3,3-dimethyl-2-oxo-5-(trifluoromethyl)indol-1-yl]acetic acid (80 mg, 0.279 mmol, 1 equiv), methyl 4-amino-4-methylpentanoate (48.5 mg, 0.335 mmol, 1.2 equiv), [bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (127 mg, 0.335 mmol, 1.2 equiv), triethylamine (TEA) (84.5 mg, 0.837 mmol, 3 equiv), and N,N-dimethylformamide (DMF) (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was extracted with ethyl acetate (EtOAc) (3 × 8 mL). The combined organic layers were washed with water (4 × 10 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1:1) to afford methyl 4-{2-[3,3-dimethyl-2-oxo-5-(trifluoromethyl)indol-1-yl]acetamido}-4-methylpentanoate (hereinafter also referred to as methyl 4-(2-(3,3-dimethyl-2-oxo-5-(trifluoromethyl)indolin-1-yl)acetamido)-4-methylpentanoate; Compound 8-OMe) (80 mg, yield 69%) as a yellow oil. LCMS: (ES, m / z): RT = 1.09 min, m / z = 415.1 [M+H] + .

[0474] Procedure 5: To an 8 mL vial were added methyl 4-{2-[3,3-dimethyl-2-oxo-5-(trifluoromethyl)indol-1-yl]acetamido}-4-methylpentanoate (60 mg, 0.145 mmol, 1 equiv), lithium hydroxide (10.4 mg, 0.435 mmol, 3 equiv), methanol (MeOH) (1 mL), and water (1 mL) at room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (8 mL). The mixture was acidified to pH 3 with HCl (2 aqueous solution). The resulting mixture was extracted with ethyl acetate (EtOAc) (3 × 8 mL). The combined organic layers were washed with water (4 × 7 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The crude product (30 mg) was purified by preparative HPLC (XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: acetonitrile (MeCN); flow rate: 60 mL / min; gradient: 19% B - 29% B in 8 min, 29% B; wavelength: 254 nm; HPLC RT (min): 7) to give 4-(2-(3,3-dimethyl-2-oxo-5-(trifluoromethyl)indolin-1-yl)acetamido)-4-methylpentanoic acid (Compound 8) (19.5 mg) as a white solid. LCMS: (ES, m / z): RT = 0.67 min, m / z = 401.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 7.77 (d, J = 1.9 Hz, 1H), 7.64 - 7.57 (m, 1H), 7.01 (d, J = 8.2 Hz, 1H), 4.31 (s, 2H), 2.18 (t, J = 8.0 Hz, 2H), 1.84 (m, J = 9.1, 6.9 Hz, 2H), 1.34 (s, 6H), 1.23 (s, 6H).

[0475] Example 5: 4-(2-(5-Cyclopropyl-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)-4-methylpentanoic acid (Compound 9) and methyl 4-(2-(5-cyclopropyl-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)-4-methylpentanoate (Compound 9-OMe) [Chemical formula] Step 1: In an 8 mL sealed tube, methyl 2-(5-bromo-3,3-dimethyl-2-oxoindol-1-yl)acetate (150 mg, 0.48 mmol, 1 equivalent), cyclopropylboronic acid (206 mg, 2.4 mmol, 5 equivalents), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl 2 )(70.3 mg, 0.09 mmol, 0.2 equivalent), Na 2 CO 3 (153 mg, 1.44 mmol, 3 equivalents), dioxane (1.5 mL), and H 2 O (0.3 mL) were added. The resulting mixture was stirred at 60 °C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with ethyl acetate (EtOAc) (3 × 3 mL). The combined organic layers were washed with water (3 × 2 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give methyl 2-(5-cyclopropyl-3,3-dimethyl-2-oxoindol-1-yl)acetate (95 mg, 43% yield) as a yellow oil. LCMS: (ES, m / z): RT = 1.57 min, m / z = 274 [M+1] + .

[0476] Step 2: In an 8 mL vial, methyl 2-(5-cyclopropyl-3,3-dimethyl-2-oxoindol-1-yl)acetate (140 mg, 0.51 mmol, 1 equivalent), methanol (MeOH) (1.5 mL), H 2O (0.30 mL) and LiOH (24.5 mg, 1.02 mmol, 2 equiv) were added. The resulting solution was stirred at 25 °C for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product (5-cyclopropyl-3,3-dimethyl-2-oxoindol-1-yl)acetic acid was used directly in the next step without further purification. LCMS: (ES, m / z): RT = 0.77 min, m / z = 260 [M+1] + .

[0477] Step 3: To a 25 mL sealed tube were added (5-cyclopropyl-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (150 mg, 0.57 mmol, 1 equiv), methyl 4-amino-4-methylpentanoate (101 mg, 0.69 mmol, 1.2 equiv), [bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (264 mg, 0.69 mmol, 1.20 equiv), N,N-dimethylformamide (DMF) (1.50 mL), and triethylamine (TEA) (176 mg, 1.73 mmol, 3 equiv). The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The reaction was quenched by the addition of water (3 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (EtOAc) (3 × 5 mL). The combined organic layers were washed with water (3 × 5 mL) and dried over anhydrous Na 2 SO 4 4-[2-(5-cyclopropyl-3,3-dimethyl-2-oxoindol-1-yl)acetamido]-4-methylpentanoic acid methyl ester (hereinafter also referred to as 4-(2-(5-cyclopropyl-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)-4-methylpentanoic acid methyl ester; Compound 9-OMe) (130 mg, yield 41%) as a pale yellow oil was obtained by purifying the residue by preparative TLC (petroleum ether / ethyl acetate 1:1). LCMS: (ES, m / z): RT = 0.92 min, m / z = 387 [M+1] + .

[0478] Step 4: To an 8 mL vial, add methyl 4-[2-(5-cyclopropyl-3,3-dimethyl-2-oxoindol-1-yl)acetamido]-4-methylpentanoate (120 mg, 0.31 mmol, 1 equiv), LiOH (14.9 mg, 0.62 mmol, 2 equiv), H 2 O (0.20 mL), and methanol (MeOH) (1 mL). Stir the resulting mixture at room temperature for 2 h. Monitor the reaction by LCMS. Extract the resulting mixture with ethyl acetate (EtOAc) (3 × 4 mL). Wash the combined organic layers with water (3 × 4 mL) and dry over anhydrous Na 2 SO 4 . After filtration, concentrate the filtrate under reduced pressure. Purify the residue by preparative TLC (DCM / MeOH (9:1)) to obtain 4-[2-(5-cyclopropyl-3,3-dimethyl-2-oxoindol-1-yl)acetamido]-4-methylpentanoic acid (120 mg, purity 62%) as a yellow oil. Purify the crude product by preparative HPLC (2#SHIMADZU (HPLC-01): XBridge Prep OBD C18 Column, 19*250 mm, 5 μm, mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: methanol (MeOH); flow rate: 20 mL / min; gradient: 54%B - 54%B, 54%B in 12 min; wavelength: 254 / 220 nm) to obtain 4-(2-(5-cyclopropyl-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)-4-methylpentanoic acid (Compound 9) (9.1 mg, yield 8%) as a white solid. LCMS: (ES, m / z): RT = 0.80 min, m / z = 373[M+1] + . 1 H NMR (400 MHz, methanol-d 4)δ 7.05 (d, J = 1.9 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 4.33 (s, 2H), 2.26 (t, J = 7.8 Hz, 2H), 1.99 (t, J = 7.9 Hz, 2H), 1.92 (d, J = 8.7 Hz, 1H), 1.37 (d, J = 15.5 Hz, 12H), 0.98 - 0.89 (m, 2H), 0.69 - 0.60 (m, 2H).

[0479] Example 6: 4-(1-(5-Bromo-3,3-dimethyl-2-oxoindolin-1-yl)cyclopropane-1-carboxamido)butanoic acid (Compound 15) and methyl 4-(1-(5-bromo-3,3-dimethyl-2-oxoindolin-1-yl)cyclopropane-1-carboxamido)butanoate (Compound 15-OMe)

Chemical formula

[0480] Procedure 2: To a 50 mL three-necked round-bottom flask purged and maintained in an inert atmosphere of nitrogen were added sodium tert-butoxide (t-BuONa) (119 mg, 1.2 mmol, 2 equiv) and dimethyl sulfoxide (DMSO) (5 mL). Subsequently, trimethylsulfoxonium iodide (271 mg, 1.234 mmol, 2 equiv) was added dropwise with stirring at 0 °C. To this was added methyl 2-(5-bromo-3,3-dimethyl-2-oxoindol-1-yl)prop-2-enoate (200 mg, 0.617 mmol, 1 equiv) in tetrahydrofuran (THF) (1 mL) within 1 hour at 0 °C. The resulting solution was stirred at 0 °C for 6 hours. The progress of the reaction was monitored by LCMS. The resulting mixture was extracted with ethyl acetate (EtOAc) (3 × 3 mL). The combined organic layers were washed with water (3 × 3 mL) and dried over anhydrous MgSO 4 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1:1) to afford methyl 1-(5-bromo-3,3-dimethyl-2-oxoindol-1-yl)cyclopropane-1-carboxylate (10 mg, yield 4.3%) as a white solid. LCMS: (ES, m / z): RT = 1.11, m / z = 338.0 [M+H] + .

[0481] Procedure 3: To an 8 mL vial were added methyl 1-(5-bromo-3,3-dimethyl-2-oxoindol-1-yl)cyclopropane-1-carboxylate (20 mg, 0.059 mmol, 1 equiv), methanol (MeOH) (0.5 mL), and H 2 2O (0.1 mL). The resulting solution was stirred at 25 °C for 2 hours. The progress of the reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product, methyl 1-(5-bromo-3,3-dimethyl-2-oxoindol-1-yl)cyclopropane-1-carboxylate, was used directly in the next step without further purification. LCMS: (ES, m / z): RT = 0.82, m / z = 323.9 [M+H] + .

[0482] Procedure 4: In an 8 mL vial, 1-(5-bromo-3,3-dimethyl-2-oxoindol-1-yl)cyclopropane-1-carboxylic acid (30 mg, 0.093 mmol, 1 equiv), methyl 4-aminobutanoate hydrochloride (17.1 mg, 0.112 mmol, 1.2 equiv), [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (42.2 mg, 0.112 mmol, 1.2 equiv), triethylamine (TEA) (18.7 mg, 0.186 mmol, 2 equiv), and N,N-dimethylformamide (DMF) (1 mL) were added. The resulting solution was stirred at 25 °C for 2 h. The progress of the reaction was monitored by LCMS. The resulting mixture was extracted with ethyl acetate (EtOAc) (3 × 3 mL). The combined organic layers were washed with water (3 × 3 mL) and dried over anhydrous MgSO 4 4-{[1-(5-bromo-3,3-dimethyl-2-oxoindol-1-yl)cyclopropyl]formamido}butanoic acid methyl ester (hereinafter also referred to as methyl 4-(1-(5-bromo-3,3-dimethyl-2-oxoindolin-1-yl)cyclopropane-1-carboxamido)butanoate; Compound 15-OMe) (13 mg, yield 32%) was obtained as a white solid. LCMS: (ES, m / z): RT = 1.12, m / z = 423.1 [M + H] + .

[0483] Procedure 5: In an 8 mL vial, 4-{[1-(5-bromo-3,3-dimethyl-2-oxoindol-1-yl)cyclopropyl]formamido}butanoic acid methyl ester (10 mg, 0.024 mmol, 1 equiv), LiOH (2.83 mg, 0.120 mmol, 5 equiv), methanol (MeOH) (0.5 mL), and H 2O (0.1 mL) was added. The resulting solution was stirred at 25 °C for 2 hours. The progress of the reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was acidified / basified / neutralized to pH 5 with concentrated HCl. The resulting mixture was extracted with ethyl acetate (EtOAc) (3 × 3 mL). The combined organic layers were washed with water (1 × 3 mL) and dried over anhydrous MgSO 4 4-{[1-(5-Bromo-3,3-dimethyl-2-oxoindol-1-yl)cyclopropyl]formamido}butanoic acid (7.2 mg) was obtained, which was purified by reverse-phase chromatography (Xselect CSH C18 OBD Column, 30*150 mm 5 μm, n; mobile phase A: acetonitrile (MeCN), mobile phase B: water (0.05% TFA); flow rate: 60 mL / min; gradient: 34% B - 44% B in 10 min, 44% B; wavelength: 254 / 220 nm; RT1 (min): 7.17; number of measurements: 0) to give the trifluoroacetic acid (TFA) salt of 4-(1-(5-bromo-3,3-dimethyl-2-oxoindolin-1-yl)cyclopropane-1-carboxamido)butanoic acid (Compound 15) (also referred to herein as 4-{[1-(5-bromo-3,3-dimethyl-2-oxoindol-1-yl)cyclopropyl]formamido}butanoic acid) (7.2 mg, 58% yield) as a white solid. LCMS: (ES, m / z): RT = 0.68, m / z = 409.0 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.00 (s, 1H), 7.68 (t, J = 5.9 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.44 (dd, J = 8.3, 2.1 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 3.04 (q, J = 6.7 Hz, 2H), 2.13 (t, J = 7.4 Hz, 2H), 1.58 (dd, J = 14.5, 7.4 Hz, 4H), 1.21 (d, J = 75.7 Hz, 8H).

[0484] Example 7: 4-(2-(5-Bromo-7-hydroxy-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoic acid (Compound 16) and 4-(2-(5-Bromo-7-hydroxy-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoic acid (Compound 16-OMe)

Chemical formula

[0485] Procedure 2: To a solution of 5-bromo-7-iodo-3,3-dimethyl-1H-indole-2-one (500 mg, 1.36 mmol, 1 equiv) in N,N-dimethylformamide (DMF) (10 mL) was added NaH (60% in mineral oil) (164 mg, 4.09 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. Then, tert-butyl 2-bromoacetate (320 mg, 1.63 mmol, 1.2 equiv) was added dropwise to the above solution at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated NH 4 Cl (20 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (EtOAc) (5 × 20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give tert-butyl 2-(5-bromo-7-iodo-3,3-dimethyl-2-oxoindol-1-yl)acetate (500 mg, 76% yield) as a yellow-green solid. LCMS: (ES, m / z): RT = 0.92 min, m / z = 480 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.83 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 4.74 (s, 1H), 4.02 (s, 1H), 1.43 (d, J = 2.5 Hz, 9H), 1.31 (s, 6H).

[0486] Procedure 3: To a stirred solution of tert-butyl 2-(5-bromo-7-iodo-3,3-dimethyl-2-oxoindol-1-yl)acetate (500 mg, 1.04 mmol, 1 equiv) in pyridine (4 mL) and H 2 O (8 mL) were added NaOH (208 mg, 5.20 mmol, 5 equiv), followed by copper(I) oxide (Cu 2(29.8 mg, 0.20 mmol, 0.2 eq) was added at room temperature. The resulting mixture was stirred at 110 °C for 12 h. The resulting mixture was filtered and the filtrate was neutralized to pH 2 with 1 N aqueous HCl. The resulting mixture was extracted with ethyl acetate (EtOAc) (5 × 20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography to give (5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (200 mg, 52% yield) as a brown solid. LCMS: (ES, m / z): RT = 0.70 min, m / z = 314 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 6) δ 12.12 (s, 1H), 7.02 (d, J = 1.9 Hz, 1H), 6.87 - 6.82 (m, 1H), 4.37 (s, 1H), 4.04 (d, J = 7.1 Hz, 1H), 1.25 (s, 6H).

[0487] Step 4: To a stirred solution of (5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (100 mg, 0.31 mmol, 1 eq) and methyl 4-aminobutyrate (44.8 mg, 0.38 mmol, 1.2 eq) in N,N-dimethylformamide (DMF) (2.5 mL) was added triethylamine (TEA) (96.6 mg, 0.95 mmol, 3 eq), followed by [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (145.25 mg, 0.38 mmol, 1.2 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The resulting mixture was extracted with ethyl acetate (EtOAc) (5 × 20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4It was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1:1) to give 2-(5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)-N-(4-methoxy-4,4-dioxobutyl)acetamide (also referred to herein as 4-(2-(5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoic acid; Compound 16-OMe) (65 mg, yield 48%) as an off-white solid. LCMS: (ES, m / z): RT = 0.52 min, m / z = 413 [M+H] + .

[0488] Step 5: To a solution of 2-(5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)-N-(4-methoxy-4,4-dioxobutyl)acetamide (50 mg, 0.116 mmol, 1 equiv) in methanol (MeOH) (2 mL) and H 2 O (0.5 mL) was added LiOH (8.37 mg, 0.35 mmol, 3 equiv). The resulting mixture was stirred at room temperature for 3 h. The reaction was monitored by LCMS. The mixture was acidified to pH 2 with 1N aqueous HCl. The resulting mixture was extracted with ethyl acetate (EtOAc) (5 × 20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase, water (10 mmol / L NH 4 HCO 3 ) and acetonitrile (MeCN) (10% to a maximum of 22% in 10 min); detector, UV254 nm) to give 4-(2-(5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoic acid (Compound 16) (26.3 mg, yield 55%) as a white solid. LCMS: (ES, m / z): RT = 0.67 min, m / z = 399.00 [M+H] + . 11H NMR (400 MHz, DMSO-d 6 ) δ 7.95 (s, 1H), 6.99 (s, 1H), 6.80 (s, 1H), 4.42 (s, 2H), 3.05 (d, J = 5.9 Hz, 2H), 2.17 (s, 2H), 1.62 (d, J = 7.0 Hz, 2H), 1.26 (s, 6H).

[0489] Example 8: 4-(2-(5-Bromo-7-fluoro-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoic acid (Compound 24) and Methyl 4-(2-(5-bromo-7-fluoro-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoate (Compound 24-OMe) [Chemical formula] Step 1: To a solution of 7-fluoro-1,3-dihydroindol-2-one (2 g, 13.23 mmol, 1 equiv) and lithium chloride (1.40 g, 33.08 mmol, 2.5 equiv) in tetrahydrofuran (THF) (40 mL) at 0 °C, n-butyllithium (n-BuLi) (2.5 M in hexane, 10.5 ml, 26.46 mmol, 2 equiv) was added dropwise under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 30 minutes. Then, methyl iodide (MeI) (4.69 g, 33.08 mmol, 2.5 equiv) was added slowly, and the mixture was stirred at 0 °C for 2 hours and then further stirred at ambient temperature for 16 hours. The reaction was monitored by LCMS. The reaction was quenched with saturated NH 4 Cl (40 mL). The aqueous layer was extracted with ethyl acetate (EtOAc) (4 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (C18 silica gel; mobile phase, MeCN in water, gradient of 10% - 50% in 30 minutes; detector, UV254 nm) to obtain 7-fluoro-3,3-dimethyl-1H-indol-2-one (1.3 g, 54% yield) as a brown solid. LCMS: (ES, m / z): RT = 0.73 min, m / z = 180 [M + H]+ . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 10.81 (s, 1H), 7.15 (dd, J = 7.3, 1.1 Hz, 1H), 7.08 (m, J = 10.4, 8.5, 1.1 Hz, 1H), 6.98 (m, J = 8.4, 7.3, 4.8 Hz, 1H), 1.27 (s, 6H).

[0490] Step 2: To a solution of 7-fluoro-3,3-dimethyl-1H-indol-2-one (1 g, 5.58 mmol, 1 equiv) in acetic acid (AcOH) (4 mL) and dichloromethane (DCM) (40 mL) was added bromine (Br 2 )(892 mg, 5.58 mmol, 1 equiv) dropwise over 4 minutes at 0 °C. The resulting mixture was stirred for an additional 2 hours at room temperature. The reaction was monitored by LCMS. The reaction was quenched with saturated aqueous NaHSO 3 at 0 °C (20 mL). The aqueous layer was extracted with ethyl acetate (EtOAc) (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (4:1) to afford 5-bromo-7-fluoro-3,3-dimethyl-1H-indol-2-one (1.10 g, 73% yield) as a yellow solid. LCMS: (ES, m / z): RT = 0.83 min, m / z = 258 [M + H] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ 10.97 (s, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.41 (dd, J = 9.8, 1.8 Hz, 1H), 1.28 (s, 6H).

[0491] Step 3: To a solution of 5-bromo-7-fluoro-3,3-dimethyl-1H-indol-2-one (500 mg, 1.93 mmol, 1 equiv) in N,N-dimethylformamide (DMF) (30 mL) was added K 2 CO 3(535 mg, 3.87 mmol, 2 equiv) and ethyl bromoacetate (388 mg, 2.32 mmol, 1.2 equiv) were added at 0 °C. The resulting mixture was stirred at room temperature for an additional 2 h. The progress of the reaction was monitored by LCMS. The resulting solution was diluted with water (200 mL) and extracted with ethyl acetate (EtOAc) (4 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na 2 SO 4 . The filtrate was concentrated under reduced pressure after filtration. The residue was purified by reverse flash chromatography (C18 silica gel; mobile phase, MeCN in water, gradient of 10% - 50% in 10 min; detector, UV 254 nm) to give ethyl 2-(5-bromo-7-fluoro-3,3-dimethyl-2-oxoindol-1-yl)acetate (550 mg, 78% yield) as a pale yellow solid. LCMS: (ES, m / z): RT = 1.03 min, m / z = 344 [M+H] + .

[0492] Step 4: To a solution of ethyl 2-(5-bromo-7-fluoro-3,3-dimethyl-2-oxoindol-1-yl)acetate (100 mg, 0.20 mmol, 1 equiv) in methanol (MeOH) (5 mL) and water (1 mL) was added LiOH (13.9 mg, 0.58 mmol, 2 equiv). The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure and dissolved in water (5 mL). The mixture residue was acidified to pH 5 with 1 N aqueous HCl. The precipitated solid was collected by filtration and washed with H 2 O (20 mL). This gave (5-bromo-7-fluoro-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (85 mg, 88% yield) as a white solid. LCMS: (ES, m / z): RT = 0.84 min, m / z = 316 [M+H] + .

[0493] Procedure 5: To a solution of (5-bromo-7-fluoro-3,3-dimethyl-2-oxoindolin-1-yl)acetic acid (100 mg, 0.31 mmol, 1 equiv) in N,N-dimethylformamide (DMF) (3 mL) was added methyl 4-aminobutyrate (44.5 mg, 0.37 mmol, 1.2 equiv), triethylamine (TEA) (96 mg, 0.94 mmol, 3 equiv), and [bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (132 mg, 0.34 mmol, 1.1 equiv). The resulting mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by LCMS. The resulting mixture was diluted with H 2 O (40 mL). The aqueous layer was extracted with ethyl acetate (EtOAc) (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (3:2) to afford methyl 4-[2-(5-bromo-7-fluoro-3,3-dimethyl-2-oxoindolin-1-yl)acetamido]butyrate (also referred to as methyl 4-(2-(5-bromo-7-fluoro-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butyrate; Compound 24-OMe) (120 mg, 87% yield) as a pale yellow solid. LCMS: (ES, m / z): RT = 0.87 min, m / z = 415 [M+H] + .

[0494] Procedure 6: H 2A solution of methyl 4-[2-(5-bromo-7-fluoro-3,3-dimethyl-2-oxoindol-1-yl)acetamido]butanoate (150 mg, 0.36 mmol, 1 equiv) in O (0.40 mL) and methanol (MeOH) (2 mL) was added with LiOH (17.3 mg, 0.72 mmol, 2 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The mixture residue was acidified to pH 4 with 1N aqueous HCl. The aqueous layer was extracted with ethyl acetate (EtOAc) (4 × 20 mL). The combined organic layers were washed with brine (1 × 20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (2#SHIMADZU (HPLC-01)): column: XSelect CSH C18 OBD Column, 30*150mm 5μm; mobile phase A: acetonitrile (MeCN), mobile phase B: water (0.05% TFA); flow rate: 60 mL / min; gradient: 30%B - 38%B in 10 min, 38%B; wavelength: 254 / 220 nm) to obtain 4-(2-(5-bromo-7-fluoro-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoic acid (Compound 24) (53.2 mg, yield 37%) as a white solid. LCMS: (ES, m / z): RT = 0.73 min, m / z = 401[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (t, J = 5.6 Hz, 1H), 7.53 (d, J = 1.7 Hz, 1H), 7.43 (dd, J = 11.0, 1.8 Hz, 1H), 4.35 (d, J = 1.8 Hz, 2H), 3.09 (m, 2H), 2.22 (t, J = 7.4 Hz, 2H), 1.63 (m, 2H), 1.32 (s, 6H).

[0495] Example 9: 4-(2-(5-Bromo-7-methoxy-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoic acid (Compound 27) and methyl 4-(2-(5-bromo-7-methoxy-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoate (Compound 27-OMe)

Chem.

[0496] Step 2: Methanol (MeOH) (5 mL) and H 2A solution of methyl 2-(5-bromo-7-methoxy-3,3-dimethyl-2-oxoindol-1-yl)acetate (120 mg, 0.35 mmol, 1 equiv) in O(1 mL) was added with NaOH (28.1 mg, 0.70 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for 2 h under an air atmosphere at room temperature. The progress of the reaction was monitored by LCMS. After the reaction was completed, the residue was concentrated under reduced pressure, redissolved in water (5 mL), and then acidified to pH = 4 with 1 N aqueous HCl solution. The resulting mixture was extracted with ethyl acetate (EtOAc) (5 × 20 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. Thereby, (5-bromo-7-methoxy-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (110 mg, yield 96%) was obtained as a white solid. LCMS: (ES, m / z): RT = 1.20 min, m / z = 328 [M+H] + .

[0497] Step 3: To a solution of (5-bromo-7-methoxy-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (90 mg, 0.27 mmol, 1 equiv) and methyl 4-aminobutanoate (38.6 mg, 0.33 mmol, 1.2 equiv) in N,N-dimethylformamide (DMF) (3 mL) was added triethylamine (TEA) (55.5 mg, 0.55 mmol, 2 equiv), followed by [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (125 mg, 0.33 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for 2 h under an air atmosphere at room temperature. The progress of the reaction was monitored by LCMS. After the reaction was completed, the resulting mixture was diluted with H 2 O (10 mL), and the resulting mixture was extracted with ethyl acetate (EtOAc) (3 × 20 mL). The combined organic layers were washed with brine (1 × 15 mL) and dried over anhydrous Na 2 SO 4It was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give methyl 4-[2-(5-bromo-7-methoxy-3,3-dimethyl-2-oxoindol-1-yl)acetamido]butanoate (also referred to as methyl 4-(2-(5-bromo-7-methoxy-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoate, Compound 27-OMe) (90 mg, yield 77%) as a white solid. LCMS: (ES, m / z): RT = 1.25 min, m / z = 427 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.01 (t, J = 5.6 Hz, 1H), 7.24 (d, J = 1.6 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H), 4.40 (s, 2H), 3.75 (s, 3H), 3.59 (s, 3H), 3.08 (q, J = 6.4 Hz, 2H), 2.32 (t, J = 7.2 Hz, 2H), 1.67 (p, J = 7.2 Hz, 2H), 1.28 (s, 6H).

[0498] Step 4: To a solution of methyl 4-[2-(5-bromo-7-methoxy-3,3-dimethyl-2-oxoindol-1-yl)acetamido]butanoate (85 mg, 0.20 mmol, 1 equiv) in methanol (MeOH) (2 mL) and H 2 O (0.5 mL) was added NaOH (15.9 mg, 0.40 mmol, 2 equiv) at room temperature. The resulting mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by LCMS. After the reaction was complete, the residue was concentrated under reduced pressure, redissolved in water (10 mL), and then acidified to pH = 4 with 1N aqueous HCl. The resulting mixture was extracted with ethyl acetate (EtOAc) (5 × 20 mL). The combined organic layers were washed with brine (1 × 10 mL) and anhydrous Na 2 SO 4It was dried. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: XSelect CSH Prep C18 OBD Column, 19 * 250 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: acetonitrile (MeCN); flow rate: 25 mL / min; gradient: 42% B to 42% B in 8 minutes, 42% B; wavelength: 254 nm; HPLC RT (min): 7.6) to obtain 4-(2-(5-bromo-7-methoxy-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoic acid (Compound 27) (43.0 mg, yield 54%) as a white solid. LCMS: (ES, m / z): RT = 1.41 min, m / z = 413 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.04 (s, 1H), 8.02 (t, J = 5.6 Hz, 1H), 7.24 (d, J = 1.6 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H), 4.39 (s, 2H), 3.75 (s, 3H), 3.08 (q, J = 6.4 Hz, 2H), 2.23 (t, J = 7.2 Hz, 2H), 1.63 (d, J = 7.2 Hz, 2H), 1.28 (s, 6H).

[0499] Example 10: 4-(2-(7-Hydroxy-5-iodo-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoic acid (Compound 28) and methyl 4-(2-(7-hydroxy-5-iodo-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoate (Compound 28-OMe)

Chemical formula

[0500] Step 2: A solution of methyl 4-[2-(5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetamido]butanoate (150 mg, 0.36 mmol, 1 equiv), methyl[2-(methylamino)ethyl]amine (64.0 mg, 0.72 mmol, 2 equiv), and NaI (435 mg, 2.90 mmol, 8 equiv) in dioxane (8 mL) was stirred under a nitrogen atmosphere at 120 °C for 2 h. The progress of the reaction was monitored by LCMS. The reaction was quenched by the addition of water (30 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (EtOAc) (3 × 20 mL) and dried over anhydrous Na 2SO 4 It was dried with. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (3:2) to give methyl 4-[2-(7-hydroxy-5-iodo-3,3-dimethyl-2-oxoindol-1-yl)acetamido]butanoate (also referred to as methyl 4-(2-(7-hydroxy-5-iodo-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoate, Compound 28-OMe) (100 mg, 60% yield) as a yellow oil. LCMS: (ES, m / z): RT = 0.778 min, m / z = 460.9 [M+H] + .

[0501] Step 3: A solution of methyl 4-[2-(7-hydroxy-5-iodo-3,3-dimethyl-2-oxoindol-1-yl)acetamido]butanoate (80.0 mg, 0.17 mmol, 1 equiv), and NaOH (104 mg, 2.61 mmol, 15.0 equiv) in methanol (3 mL) and water (3 mL) was stirred at room temperature for 1 hour. The progress of the reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure. The reaction was dissolved by the addition of water (20 mL) at room temperature. The residue was acidified to pH 6 with 2N HCl (aqueous solution). The aqueous layer was extracted with ethyl acetate (EtOAc) (3 × 20 mL), and anhydrous Na 2 SO 4 ​It was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (3:7) to obtain 4-(2-(7-hydroxy-5-iodo-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoic acid (80 mg, purity 85%) as a yellow oil, which was further purified by preparative HPLC (column: XBridge Prep Phenyl OBD Column, 19*250 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: acetonitrile (MeCN); flow rate: 25 mL / min; gradient: 30% B - 40% B in 10 minutes, 40% B; wavelength: 254 nm; HPLC RT (min): 9) to obtain 4-(2-(7-hydroxy-5-iodo-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoic acid (Compound 28) (39.9 mg, yield 66%) as a white solid. LCMS: (ES, m / z): RT = 1.295 min, m / z = 446.9 [M + H]+. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.03 (s, 1H), 9.96 (s, 1H), 7.97 (t, J = 5.6 Hz, 1H), 7.18 (d, J = 1.6 Hz, 1H), 7.01 (d, J = 1.6 Hz, 1H), 4.43 (s, 2H), 3.07 (q, J = 6.6 Hz, 2H), 2.22 (t, J = 7.4 Hz, 2H), 1.62 (p, J = 7.3 Hz, 2H), 1.26 (s, 6H).

[0502] Example 11: N-(3-(1H-Tetrazol-5-yl)propyl)-2-(5-cyclopropyl-7-hydroxy-3,3-dimethyl-2-oxoindolin-1-yl)acetamide (tautomer 1) and N-(3-(2H-Tetrazol-5-yl)propyl)-2-(5-cyclopropyl-7-hydroxy-3,3-dimethyl-2-oxoindolin-1-yl)acetamide (tautomer 2) (Compound 29)

Chemical Structure

[0503] Procedure 2: To a solution of methyl 2-(5-bromo-7-hydroxy-3,3-dimethyl-2-oxoindolin-1-yl)acetate (125 mg, 0.52 mmol, 1 equiv) in tetrahydrofuran (THF) (6 mL), 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene (Q-Phos) (90.0 mg, 0.45 mmol, 0.80 equiv), bromo(cyclopropyl)zinc (0.5 M in THF), (3 mL, 1.50 mmol, 3 equiv), and tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 )(140 mg, 0.16 mmol, 0.30 equiv) were added. The resulting mixture was stirred for 1 h under a nitrogen atmosphere at 25 °C. The progress of the reaction was monitored by LCMS. The resulting mixture was H 2It was diluted with O (50 mL). The aqueous layer was extracted with ethyl acetate (EtOAc) (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 10% to 50% in 10 minutes; detector, UV 254 nm) to obtain methyl 2-(5-cyclopropyl-7-hydroxy-3,3-dimethyl-2-oxoindolin-1-yl)acetate (105 mg, yield 62%) as a brown solid. LCMS: (ES, m / z): RT = 1.20 min, m / z = 290 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.55 (s, 1H), 6.60 (d, J = 1.6 Hz, 1H), 6.40 (d, J = 1.6 Hz, 1H), 3.67 (d, J = 11.2 Hz, 4H), 1.81 (m, 1H), 1.67 - 1.42 (m, 2H), 1.32 (d, J = 7.2 Hz, 3H), 1.25 (s, 6H).

[0504] Step 3: To a solution of methyl 2-(5-cyclopropyl-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetate (105 mg, 0.38 mmol, 1 equiv) in methanol (MeOH) (5 mL) and H 2 O (1 mL), NaOH (30.4 mg, 0.76 mmol, 2 equiv) was added at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. After the reaction was complete, the residue was concentrated under reduced pressure, redissolved in water (5 mL), and then acidified to pH = 4 with 1 N aqueous HCl. The resulting mixture was extracted with ethyl acetate (EtOAc) (5 × 20 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous Na 2 SO 4It was dried. After filtration, the filtrate was concentrated under reduced pressure to obtain (5-cyclopropyl-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (95 mg, yield 91%) as a white solid. LCMS: (ES, m / z): RT = 1.25 min, m / z = 276 [M+H] + .

[0505] Step 4: To a solution of (5-cyclopropyl-7-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (80 mg, 0.31 mmol, 1 equiv) and 3-(1H-1,2,3,4-tetrazol-5-yl)propan-1-amine (46.7 mg, 0.37 mmol, 1.2 equiv) in N,N-dimethylformamide (DMF) (3 mL), triethylamine (TEA) (62 mg, 0.61 mmol, 2 equiv) was added followed by [bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (128.1 mg, 0.34 mmol, 1.1 equiv) at room temperature. The resulting mixture was stirred at 25 °C for 2 h. The reaction was monitored by LCMS. After the reaction was complete, the residue was purified by reverse flash chromatography (C18 silica gel; mobile phase, acetonitrile (MeCN) in water (0.1% FA), gradient from 10% to 50% in 10 min; detector, UV 254 nm) to obtain N-(3-(1H-tetrazol-5-yl)propyl)-2-(5-cyclopropyl-7-hydroxy-3,3-dimethyl-2-oxoindolin-1-yl)acetamide (tautomer 1) and N-(3-(2H-tetrazol-5-yl)propyl)-2-(5-cyclopropyl-7-hydroxy-3,3-dimethyl-2-oxoindolin-1-yl)acetamide (tautomer 2) (Compound 29) (9.3 mg, yield 62%) as a white solid. LCMS: (ES, m / z): RT = 1.26 min, m / z = 385 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ 8.04 (t, J = 5.6 Hz, 1H), 6.54 (d, J = 1.6 Hz, 1H), 6.43 (d, J = 1.6 Hz, 1H), 4.42 (s, 2H), 3.08 (q, J = 6.4 Hz, 2H), 2.74 (t, J = 7.2 Hz, 2H), 1.79 (m, J 1 = 8.4, J 2 = 4.4 Hz, 1H), 1.71 (q, J = 7.2, 6.8 Hz, 2H), 1.24 (s, 6H), 0.85 (m, 2H), 0.54 (m, 2H).

[0506] Example 12: 4-(2-(5-Bromo-6-hydroxy-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoic acid (Compound 36) and Methyl 4-(2-(5-bromo-6-hydroxy-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoate (Compound 36-OMe)

Chemical Structure

[0507] Step 2: To a 20 mL vial, 6-methoxy-3,3-dimethyl-1H-indol-2-one (200 mg, 1.04 mmol, 1 equiv), N,N-dimethylformamide (DMF) (8 mL), and N-bromosuccinimide (NBS) (186 mg, 1.046 mmol, 1 equiv) were added at room temperature. The resulting mixture was stirred for 2 h under a nitrogen atmosphere at room temperature. The reaction was quenched by the addition of water / ice (20 mL) at 0 °C. The aqueous layer was extracted with ethyl acetate (EtOAc) (3 × 20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (2:1) to give 5-bromo-6-methoxy-3,3-dimethyl-1H-indol-2-one (190 mg, 67% yield) as a yellow solid. LCMS (LCMS, ESI): RT = 0.735 min, m / z 270 [M+H] + . 1 1H NMR (400 MHz, DMSO-d 6 )δ 10.42(s,1H),7.50(s,1H),6.59(s,1H),3.83(s,3H),1.23(s,6H).

[0508] Step 3: A solution of 5-bromo-6-methoxy-3,3-dimethyl-1H-indol-2-one (150 mg, 0.55 mmol, 1 equiv) in tetrahydrofuran (THF) (10 mL) was treated with NaH (60% dispersion in mineral oil) (26.65 mg, 1.11 mmol, 2 equiv) for 30 minutes under a nitrogen atmosphere at 0 °C, followed by dropwise addition of ethyl bromoacetate (185 mg, 1.11 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred for 1 hour under a nitrogen atmosphere at room temperature. The progress of the reaction was monitored by LCMS. The reaction was quenched by addition of water / ice (20 mL) at 0 °C. The aqueous layer was extracted with ethyl acetate (EtOAc) (3 × 50 mL), and dried over anhydrous Na 2 SO 4 . The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to afford ethyl 2-(5-bromo-6-methoxy-3,3-dimethyl-2-oxoindol-1-yl)acetate (170 mg, 86% yield) as a yellow solid. LCMS (LCMS, ESI): RT = 928 min, m / z = 356 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.59 (s, 1H), 6.99 (s, 1H), 4.60 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 1.28 (s, 6H), 1.21 (d, J = 7.2 Hz, 3H).

[0509] Step 4: To a stirred solution of ethyl 2-(5-bromo-6-methoxy-3,3-dimethyl-2-oxoindol-1-yl)acetate (100 mg, 0.28 mmol, 1 equiv) in dichloromethane (DCM) was added BBr 3 (1 N in DCM) (0.56 mL, 0.56 mmol, 2 equiv) dropwise under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred for 1 hour under a nitrogen atmosphere at room temperature. The progress of the reaction was monitored by LCMS. The reaction was quenched with water / ice at 0 °C. The aqueous layer was extracted with ethyl acetate (EtOAc) (3 × 50 mL), and dried over anhydrous Na 2 SO 4It was dried. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1:1) to obtain (5-bromo-6-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (70 mg, yield 79%) as a yellow solid. LCMS (LCMS, ESI): RT = 667 min, m / z = 314 [M+H] + .

[0510] Step 5: To an 8 mL vial were added (5-bromo-6-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (60 mg, 0.19 mmol, 1 equiv), methyl 4-aminobutyrate (26.8 mg, 0.23 mmol, 1.2 equiv), triethylamine (TEA) (58.0 mg, 0.57 mmol, 3 equiv), and N,N-dimethylformamide (DMF) (3 mL), and [bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (87.2 mg, 0.23 mmol, 1.20 equiv) at room temperature. The resulting mixture was stirred for 1 h under a nitrogen atmosphere at room temperature. The progress of the reaction was monitored by LCMS. The residue was purified by reverse flash chromatography (C18 silica gel; mobile phase, acetonitrile (MeCN) in water (gradient from 60% to 70% in 10 min); detector, UV 254 nm) to obtain methyl 4-[2-(5-bromo-6-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetamido]butyrate (also referred to as methyl 4-(2-(5-bromo-6-hydroxy-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butyrate, Compound 36-OMe) (50 mg, yield 63%) as a yellow solid. LCMS (LCMS, ESI): RT = 705 min, m / z = 413 [M+H] + .

[0511] Procedure 6: To a 6:8 mL vial, add methyl 4-[2-(5-bromo-6-hydroxy-3,3-dimethyl-2-oxoindol-1-yl)acetamido]butanoate (50.0 mg, 0.12 mmol, 1 equiv), NaOH (9.68 mg, 0.24 mmol, 2 equiv), methanol (MeOH) (1 mL), and H 2 O (1 mL) at room temperature. Stir the resulting mixture for 2 h under an air atmosphere at room temperature. Monitor the progress of the reaction by LCMS. After the reaction is complete, concentrate the residue under reduced pressure and redissolve it in water (5 mL). Acidify the residue to pH 6 with 2 N HCl (aqueous solution), extract the aqueous layer with ethyl acetate (EtOAc) (3 × 20 mL), and then dry over anhydrous Na 2 SO 4 . After filtration, concentrate the filtrate under reduced pressure and purify the residue by reverse flash chromatography (C18 silica gel; mobile phase, acetonitrile (MeCN) in water (gradient of 10% - 30% in 10 min); detector, UV 254 nm) to obtain 4-(2-(5-bromo-6-hydroxy-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoic acid (Compound 36) (20.7 mg, 43% yield) as a white solid. LCMS (LCMS, ESI): RT = 1.211 min, m / z = 398.95 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.70 (s, 1H), 7.04 (s, 1H), 6.00 (s, 1H), 4.03 (s, 2H), 3.06 (q, J = 6.0 Hz, 2H), 1.98 (t, J = 6.9 Hz, 2H), 1.63 (dt, J = 12.0, 6.0 Hz, 2H), 1.18 (s, 6H).

[0512] Example 13: 4-(2-(5-Cyclopropyl-4-fluoro-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoic acid (Compound 56) and methyl 4-(2-(5-cyclopropyl-4-fluoro-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoate (Compound 56-OMe)

Chem.

[0513] Step 2: To a stirred solution of ethyl 2-(5-bromo-4-fluoro-3,3-dimethyl-2-oxoindol-1-yl)acetate (200 mg, 0.58 mmol, 1 equiv) and cyclopropylboronic acid (250 mg, 2.9 mmol, 5 equiv) in dioxane (5 mL) and H 2 2O (1 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex (Pd(dppf)Cl 2 2 - DCM) (85.0 mg, 0.11 mmol, 0.2 equiv), and Na 2 2CO 3(185 mg, 1.74 mmol, 3 equiv) was added. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (20 mL). The aqueous layer was extracted with ethyl acetate (EtOAc) (3 × 20 mL). The combined organic layers were washed with brine (1 × 20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to afford ethyl 2-(5-cyclopropyl-4-fluoro-3,3-dimethyl-2-oxoindolin-1-yl)acetate (90 mg, 48% yield) as an off-white solid. LCMS: (ES, m / z): RT = 1.03 min, m / z = 306 [M + H] + .

[0514] Step 3: To a stirred solution of ethyl 2-(5-cyclopropyl-4-fluoro-3,3-dimethyl-2-oxoindolin-1-yl)acetate (100 mg, 0.32 mmol, 1 equiv) in MeOH (5 mL) and H 2 O (1 mL) was added LiOH (39.2 mg, 1.63 mmol, 5 equiv). The resulting solution was stirred at room temperature for 2 h. The progress of the reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (4 mL) and the mixture was adjusted to pH = 5 with HCl (1 M aqueous solution). The precipitated solid was collected by filtration and washed with water (3 × 5 mL) to afford (5-cyclopropyl-4-fluoro-3,3-dimethyl-2-oxoindolin-1-yl)acetic acid (80 mg, 88% yield) as an off-white solid. LCMS: (ES, m / z): RT = 1.03 min, m / z = 278 [M + H] + .

[0515] Procedure 4: To a stirred solution of (5-cyclopropyl-4-fluoro-3,3-dimethyl-2-oxoindol-1-yl)acetic acid (100 mg, 0.36 mmol, 1 equiv) and methyl 4-aminobutyrate (50.7 mg, 0.433 mmol, 1.2 equiv) in N,N-dimethylformamide (DMF) (2 mL), triethylamine (TEA) (73.0 mg, 0.72 mmol, 2 equiv) and [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (165 mg, 0.43 mmol, 1.20 equiv) were added. The resulting solution was stirred at room temperature for 2 h. The progress of the reaction was monitored by LCMS. The obtained mixture was quenched with water (20 mL). The aqueous layer was extracted with ethyl acetate (EtOAc) (3 × 20 mL). The combined organic layers were washed with brine (1 × 20 mL) and dried over anhydrous Na 2 SO 4 . The filtrate was concentrated under reduced pressure after filtration, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (3:1) to give methyl 4-[2-(5-cyclopropyl-4-fluoro-3,3-dimethyl-2-oxoindol-1-yl)acetamido]butyrate (also referred to as methyl 4-(2-(5-cyclopropyl-4-fluoro-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butyrate; Compound 56-OMe) (120 mg, yield 71%) as a yellow oil. LCMS: (ES, m / z): RT = 0.98 min, m / z = 377 [M+H] + .

[0516] Procedure 5: MeOH (2.50 mL) and H 2To a stirred solution of 4-[2-(5-cyclopropyl-4-fluoro-3,3-dimethyl-2-oxoindol-1-yl)acetamido]butanoate (100 mg, 0.27 mmol, 1 equiv) in O (0.50 mL), LiOH (32.4 mg, 1.35 mmol, 5 equiv) was added. The resulting mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water (4 mL) and acidified to pH = 5 with HCl (1 M aqueous solution). The aqueous layer was extracted with ethyl acetate (EtOAc) (3 × 10 mL), and the combined organic layers were washed with brine (1 × 20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (Xselect CSH C18 OBD Column, 30 * 150 mm 5 μm, n; mobile phase A: acetonitrile (MeCN), mobile phase B: water (0.05% TFA); flow rate: 60 mL / min; gradient: 31% B - 41% B in 10 min; wavelength: 254 / 220 nm; HPLC RT (min): 8.53) to give 4-(2-(5-cyclopropyl-4-fluoro-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoic acid (Compound 56) (27.1 mg, yield 28%) as a white solid. LCMS: (ES, m / z): RT = 0.78 min, m / z = 363 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (t, J = 5.6 Hz, 1H), 6.89 (t, J = 7.9 Hz, 1H), 6.64 (d, J = 8.1 Hz, 1H), 4.27 (s, 2H), 3.08 (q, J = 6.6 Hz, 2H), 2.23 (t, J = 7.4 Hz, 2H), 1.98 (m, 1H), 1.64 (m, 2H), 1.38 (s, 6H), 0.96 - 0.85 (m, 2H), 0.69 - 0.61 (m, 2H).

[0517] Example 14: 4-(2-(5-Cyclopropyl-4,7-difluoro-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoic acid (Compound 57) and tert-Butyl 4-(2-(5-cyclopropyl-4,7-difluoro-3,3-dimethyl-2-oxoindolin-1-yl)acetamido)butanoate (Compound 57-OtBu) [Chemical formula] Step 1: To a stirred mixture of Zn powder (3.21 g, 49.1 mmol, 9 equivalents) in THF (100 mL) was added TiCl 4 (3.79 mL, 27.3 mmol, 5 equivalents) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C for 2 hours under a nitrogen atmosphere. To the above mixture was added 4,7-difluoro-1H-indole-2,3-dione (1 g, 5.46 mmol, 1 equivalent) by dropwise addition at room temperature. The resulting mixture was stirred at room temperature for an additional 12 hours. The reaction was monitored by LCMS. The reaction was quenched wi...

Claims

1. Compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, stereoisomer, or isotopic derivative thereof (in the formula, R １ is halo, -CN, C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ haloalkyl, C １ -C ６ alkoxy, or C ３ -C １２ cycloalkyl, and Each R ２ and R ３ However, independently, H and C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C ３ -C １２ Cycloalkyl, 3-12 membered heterocyclyl, C ６ -C １０ The aryl or 5-10 membered heteroaryl is wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more halo, -CN, -OH, amino, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, or C １ -C ６ It is optionally substituted with an alkoxy, or R ２ and R ３ However, they cyclize together with the atoms to which they are bonded, C ３ -C １２ A cycloalkyl or 3-12 membered heterocycline is formed, and the cycloalkyl or heterocycline contains one or more halo, -CN, -OH, amino, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, or C １ -C ６ It is arbitrarily substituted with alkoxy, R ４ However, -C １ -C ６ Alkyl-,-(L １ ) ｐ - (C ３ -C １２ Cycloalkyl)-,-(L １ ) ｐ - (3-12 member heterocyclyl) -, - (L １ ) ｐ - (C ６ -C １０ (aryl) -, or - (L １ ) ｐ - (5-10 member heteroaryl) - and each L １ However, independently, -(C(R Ｌ１ ) ２ ) - and furthermore, each R Ｌ１ However, independently, H, Halo, or C １ -C ３ Alkyl or two R Ｌ１ The groups, together with the atoms to which they are bonded, C ３－４ A cycloalkyl group is formed, and the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group consists of one or more halo, -CN, -OH, amino, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, or C ３ It is optionally substituted with a cycloalkyl group. Z is -(L ２ ), ｎ -(carboxylic acid) or -(L ２ ), ｎ -tetrazole, and each L ２ is independently -(C(R Ｌ２ )) ２ -, and further, each R Ｌ２ is independently H, halo, or C １ -C ３ alkyl, or two R Ｌ２ groups together with the atom to which they are attached form C ３－４ cycloalkyl, and the alkyl or cycloalkyl is optionally substituted with one or more halo, -CN, -OH, amino, C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ haloalkyl, C １ -C ６ alkoxy, or C ３ cycloalkyl). Each R ５ However, independently, Halo or C １ -C ６ It is an alkyl group, and the alkyl group comprises one or more halo, -CN, -OH, amino, and C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, or C １ -C ６ Optionally substituted with alkoxy, or both R ５ However, they cyclize together with the atoms to which they are bonded, forming one or more halos, -CN, -OH, aminos, and C atoms. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, or C １ -C ６ C is arbitrarily substituted with an alkoxy. ３ -C １２ Forming a cycloalkyl group, R ６ However, H, halo, -OH, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, or C １ -C ６ It is an alkoxy, R ６’ However, H, halo, -OH, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, or C １ -C ６ It is an alkoxy, R ６” However, H, halo, -OH, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, or C １ -C ６ It is an alkoxy, R ７ However, independently, H or C １ -C ４ It is alkyl, n is an integer of 0, 1, 2, or 3. (where p is an integer of 0, 1, or 2).

2. The compound according to claim 1 of formula (I): 【Chemistry 2】 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof (in the formula, R １ However, halo, nitrile, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, or C ３ -C １２ It is a cycloalkyl, Each R ２ and R ３ However, independently, H and C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C ３ -C １２ Cycloalkyl, 3-12 membered heterocyclyl, C ６ -C １０ The aryl or 5-10 membered heteroaryl is wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more halo, cyano, hydroxy, amino, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, or C １ -C ６ It is optionally substituted with an alkoxy, or R ２ and R ３ However, they cyclize together with the atoms to which they are bonded, C ３ -C １２ A cycloalkyl or 3-12 membered heterocycline is formed, and the cycloalkyl or heterocycline contains one or more halo, cyano, hydroxy, amino, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, or C １ -C ６ It is arbitrarily substituted with alkoxy, R ４ However, -C １ -C ６ Alkyl-,-(CH ２ ) ｐ - (C ３ -C １２ Cycloalkyl)-,-(CH ２ ) ｐ - (3-12 member heterocyclyl), C ６ -C １０ Aryl, or - (CH ２ ) ｐ - (5-10 member heteroaryl), wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more halo, cyano, hydroxy, amino, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, or C １ -C ６ It is arbitrarily substituted with alkoxy, Z is -(CH ２ ) ｎ - (carboxylic acid) or - (CH ２ ) ｎ - It is a tetrazole, Each R ５ However, independently, C １ -C ６ It is an alkyl group, and the alkyl group is one or more halo, cyano, hydroxy, amino, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, or C １ -C ６ It is optionally substituted with an alkoxy, or Both R ５ However, they cyclize together with the atoms to which they are bonded, forming one or more halo, cyano, hydroxy, amino, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, or C １ -C ６ C is arbitrarily substituted with an alkoxy. ３ -C １２ Forming a cycloalkyl group, R ６ However, H, halogen, -OH, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, or C １ -C ６ It is an alkoxy, R ６’ However, H, halogen, -OH, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, or C １ -C ６ It is an alkoxy, R ６” However, H, halogen, -OH, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, or C １ -C ６ It is an alkoxy, R ７ However, independently, H or C １ -C ４ It is alkyl, n is an integer between 0 and 3, (where p is an integer between 0 and 2).

3. R １ However, bromo, chloro, nitrile, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, or C ３ -C １２ It is a cycloalkyl, Each R ２ and R ３ However, independently, H and C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C １２ Cycloalkyl, 3-12 membered heterocyclyl, C ６ -C １０ The alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more halo, cyano, hydroxy, amino, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, or C １ -C ６ It is optionally substituted with an alkoxy, or R ２ and R ３ However, when combined into a cyclotomic structure, C ３ -C １２ A cycloalkyl or 3-12 membered heterocycline is formed, and the cycloalkyl or heterocycline contains one or more halo, cyano, hydroxy, amino, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, or C １ -C ６ It is arbitrarily substituted with alkoxy, R ４ However, n-propyl, -(CH ２ ) ｐ - (C ３ -C １２ Cycloalkyl), - (CH ２ ) ｐ - (3-12 member heterocyclyl), C ６ -C １０ Aryl, or - (CH ２ ) ｐ - (5-10 member heteroaryl), wherein the n-propyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more halo, cyano, hydroxy, amino, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, or C １ -C ６ It is arbitrarily substituted with alkoxy, Z is -(CH ２ ) ｎ - (carboxylic acid) or - (CH ２ ) ｎ - It is a tetrazole, Each R ５ However, one or more halo, cyano, hydroxy, amino, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, or C １ -C ６ C is arbitrarily substituted with an alkoxy. １ -C ６ It is alkyl, or Both R ５ However, they cyclize together with the atoms to which they are bonded, forming one or more halo, cyano, hydroxy, amino, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, or C １ -C ６ C is arbitrarily substituted with an alkoxy. ３ -C １２ Forming a cycloalkyl group, R ６ However, H, halogen, -OH, C １ -C ６ Alkyl, or C １ -C ６ It is an alkoxy, R ６’ However, H, halogen, -OH, C １ -C ６ Alkyl, or C １ -C ６ It is an alkoxy, R ６” However, H, halogen, -OH, C １ -C ６ Alkyl, or C １ -C ６ It is an alkoxy, R ７ However, independently, H or C １ -C ４ It is alkyl, n is an integer between 0 and 3, The compound according to claim 1, wherein p is an integer between 0 and 2.

4. Each R ２ and R ３ The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or isotopic derivative thereof, wherein H is present.

5. -R ４ -Z is, - The basis of equation (i): 【Transformation 3】 (wherein Z' is a tetrazole or carboxylic acid, and ring A is C ３ -C ５ It is a cycloalkyl or 4-5 membered heterocycline, and each R ４ａ However, they became independent, Hello, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, or C ３ It is a cycloalkyl group where x is 0, 1, 2, or 3, or - The basis of equation (ii): 【Chemistry 4】 (wherein Z' is a tetrazole or carboxylic acid, and ring A is C ３ -C ５ It is a cycloalkyl or 4-5 membered heterocycline, and each R ４ａ However, they became independent, Hello, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, or C ３ It is a cycloalkyl group where x is 0, 1, 2, or 3, or - The basis of equation (iii): 【Transformation 5】 (wherein Z' is a tetrazole or carboxylic acid, and ring A is C ３ -C ５ It is a cycloalkyl or 4-5 membered heterocycline, and each R ４ａ However, they became independent, Hello, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, or C ３ It is a cycloalkyl group where x is 0, 1, 2, or 3, or - The basis of equation (iv): 【Transformation 6】 (wherein Z' is a tetrazole or carboxylic acid, and each R ４ａ However, they became independent, Hello, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, or C ３ The compound according to claim 1, wherein x is cycloalkyl and x is 0, 1, 2, or 3, or a pharmaceutically acceptable salt, stereoisomer, or isotopic derivative thereof.

6. The base of the above formula (iv) is, 【Transformation 7】 The compound according to claim 5, or a pharmaceutically acceptable salt, stereoisomer, or isotopic derivative thereof.

7. -R ４ -Z is the basis of the following equation: 【Transformation 8】 (wherein Z' is a tetrazole or carboxylic acid, and each R ４ａ However, they became independent, Hello, C １ -C ３ Alkyl, C １ -C ３ The compound according to claim 1, wherein x is a haloalkyl group (where x is 0, 1, 2, or 3), or a pharmaceutically acceptable salt, stereoisomer, or isotopic derivative thereof.

8. -R ４ -Z is the basis of the following equation: 【Chemistry 9】 (wherein Z' is a tetrazole or carboxylic acid, and each R ４ａ However, they became independent, Hello, C １ -C ３ Alkyl, C １ -C ３ The compound according to claim 1, wherein x is a haloalkyl group (where x is 0, 1, 2, or 3), or a pharmaceutically acceptable salt, stereoisomer, or isotopic derivative thereof.

9. Each R ５ However, fluoro and C １ -C ６ Selected from the group consisting of alkyl groups, or both R ５ However, they cyclize together with the atoms to which they are bonded, C ３ A compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or isotopic derivative thereof, which forms a cycloalkyl group.

10. The following equation (viiii) has a 6,5-biring core: 【Chemistry 10】 However, the formula is: 【Chemistry 11】 (In the formula, R ６ , R ６’ , and R ６” The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or isotopic derivative thereof, wherein at least one of the elements is not H.

11. 6,5-Biring core, formula: 【Chemistry 12】 The compound described in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or isotopic derivative thereof.

12. The compound of formula (I) is the one with the following formula: 【Chemistry 13】 The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or isotopic derivative thereof, wherein at least one of R 6, R 6', and R 6'' is not H.

13. A compound according to claim 1, selected from the group consisting of the following: 【Chemistry 14-1】 【Chemistry 14-2】 【Chemistry 14-3】 【Chemistry 14-4】 【Chemistry 14-5】 【Chemistry 14-6】 【Chemistry 14-7】 Alternatively, any pharmaceutically acceptable salt, stereoisomer, or isotopic derivative of any of the aforementioned.

14. The following formula: 【Chemistry 15】 The compound described in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof.

15. The following formula: 【Chemistry 16】 The compound described in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof.

16. The following formula: 【Chemistry 17】 The compound described in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or isotopic isomer thereof.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, stereoisomer, or isotopic derivative thereof, and one or more pharmaceutically acceptable excipients.

18. A pharmaceutical composition according to claim 17 for treating a disease or disorder in a target area where it is needed.

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